Imidazooxadiazole compounds

ABSTRACT

The present invention provides thiazole compounds of Formula I 
                         
wherein X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and W, and ring AA, are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrugs, or esters or solvate form thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of platelet aggregation and thus can be used as medicaments for treating or preventing thromboembolic disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 62/016,161, filed Jun. 24, 2014, the entire content of which isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides novel imidazooxadiazole inhibitors ofplatelet aggregation which are useful in preventing or treatingthromboembolic disorders. This invention also relates to pharmaceuticalcompositions containing these compounds and methods of using the same.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), syntheticpentasaccharides, and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®).

Current anti-platelet therapies have limitations including increasedrisk of bleeding as well as partial efficacy (relative cardiovascularrisk reduction in the 20 to 30% range). Thus, discovering and developingsafe and efficacious oral or parenteral antithrombotics for theprevention and treatment of a wide range of thromboembolic disordersremains an important goal.

Alpha-thrombin is the most potent known activator of plateletaggregation and degranulation. Activation of platelets is causallyinvolved in atherothrombotic vascular occlusions. Thrombin activatesplatelets by cleaving G-protein coupled receptors termed proteaseactivated receptors (PARs). PARs provide their own cryptic ligandpresent in the N-terminal extracellular domain that is unmasked byproteolytic cleavage, with subsequent intramolecular binding to thereceptor to induce signaling (tethered ligand mechanism; Coughlin, S.R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic thesequence of the newly formed N-terminus upon proteolytic activation caninduce signaling independent of receptor cleavage. Platelets are a keyplayer in atherothrombotic events. Human platelets express at least twothrombin receptors, commonly referred to as PAR1 and PAR4. Inhibitors ofPAR1 have been investigated extensively, and several compounds,including vorapaxar and atopaxar have advanced into late stage clinicaltrials. Recently, in the TRACER phase III trial in ACS patients,vorapaxar did not significantly reduce cardiovascular events, butsignificantly increased the risk of major bleeding (Tricoci, P. et al.,N. Eng. J. Med., 366(1):20-33 (2012). Thus, there remains a need todiscover new antiplatelet agents with increased efficacy and reducedbleeding side effects.

There are several early reports of preclinical studies of PAR4inhibitors. Lee, F-Y. et al., “Synthesis of1-Benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole Analogues as NovelAntiplatelet Agents”, J. Med. Chem., 44(22):3746-3749 (2001) disclosesin the abstract that the compound

“was found to be a selective and potent inhibitor of protease-activatedreceptor type 4 (PAR4)-dependent platelet activation.”

Compound 58 is also referred to as YD-3 in Wu, C-C. et al., “SelectiveInhibition of Protease-activated Receptor 4-Dependent PlateletActivation by YD-3”, Thromb. Haemost., 87:1026-1033 (2002). Also, seeChen, H. S. et al., “Synthesis and antiplatelet activity of ethyl4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives”, Bioorg. Med.Chem., 16:1262-1278 (2008).

EP1166785 A1 and EP0667345 disclose various pyrazole derivatives whichare useful as inhibitors of platelet aggregation.

The PCT publications WO2013/163279, WO2013/163244, and WO2013/163241disclose various PAR4 antagonists which are useful as inhibitors ofplatelet aggregation.

SUMMARY OF THE INVENTION

It has been found that imidazooxadiazole compounds in accordance withthe present invention are PAR4 antagonists which inhibit plateletaggregation in gamma-thrombin induced platelet aggregation assays.

Accordingly, the present invention provides novel imidazooxadiazoleanalogues which are PAR4 antagonists and are useful as selectiveinhibitors of platelet aggregation, including stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs, or estersthereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugs, oresters thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs, or estersthereof.

The present invention also provides a method for the treatment orprophylaxis of thromboembolic disorders comprising administering to apatient in need of such treatment or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs, or esters thereof.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs, or esters thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs, or esters thereof, for themanufacture of a medicament for the treatment or prophylaxis of athromboembolic disorder.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION

In one embodiment, the present invention provides imidazooxazolecompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, of Formula I having the structure:

wherein:

-   -   the dashed line represents an optional double-bond    -   X¹ is O and X² is CH, CR¹⁰, or N; or    -   X¹ is N and X² is O; or    -   X¹ is N, CH, or CR¹⁰, and X² is S; or    -   X¹ is N and X² is NH; or    -   X¹ is NH and X² is CH or CR¹⁰; or    -   X¹ is CH or CR¹⁰ and X² is NH;    -   X³, X⁴ and X⁵ are independently selected from CR³ or N;    -   W is O or S;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₂ alkoxy-C₁-C₂ alkyl,        -   tetrahydrofuran-2-yl;        -   C₁-C₄ alkylthio,        -   C₁-C₄ alkylNH—,        -   (C₁-C₄ alkyl)₂N—,        -   halo-C₁-C₂-alkyl, where halo is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R² is selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy, and        -   halo-C₁-C₂-alkyl, where halo is F or Cl, and        -   cyano;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio,        halo, OH, CN, OCF₃, OCHF₂, OCH₂F, C₁-C₂-alkoxy-C₁-C₂-alkoxy,        halo-C₁-C₃-alkyl, benzyloxy substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, and        —(CH₂)_(n)-phenyl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        OCHF₂, di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁₋₄        hydroxyalkyl, C₁₋₄ fluoroalkyl or R⁴ and R⁵ can be taken        together with the carbon to which they are attached to form a        C₃-C₇ cycloalkyl ring;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one O, N or S atom, or a 6-memberedheteroaryl ring, containing at least one nitrogen atom;

-   -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, S(═O)₂NR¹¹R¹², and C₁-C₅        alkyl substituted by 0 to 7 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where    -   D is a linker, which is selected from a single bond, —O—, —S—,

C₁-C₄ alkylene substituted by 0 to 4 groups independently selected fromhalo or OH, C₁-C₄ alkyleneoxy, C₁-C₄ alkylenethio, C₁-C₄alkyleneoxy-C₁-C₄-alkylene, C₁-C₄-alkylenethio-C₁-C₄-alkylene,—S—C₁-C₄-alkylene, —O—C₁-C₄-alkylene, and C₂-C₆ alkenylene,

-   -   B is selected from the group consisting of a C₆-C₁₀ aryl, a 5-        to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl        containing carbon atoms and 1 to 4 additional heteroatoms        selected from N, O, and S, a C₃-C₅ cycloalkyl which may contain        unsaturation and a C₅-C₁₁ spirocycloalkyl which may contain        unsaturation and optionally containing 1 to 3 heteroatoms        selected from O, N or S, all of which may be optionally        substituted with one or more R^(b), R^(c), R^(d) and R^(e);    -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from the group consisting of halo,        halo-C₁-C₄ alkoxy, OH, CN, NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy,        C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄        alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,        S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, SO₂R¹⁴,        N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹²,        O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₃-C₆ cycloalkyl, a 4- to        10-membered heterocyclyloxy; a C₁-C₅ alkyl substituted by 0 to 7        groups independently selected from halo, CF₃, OCF₃, OH, CN,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to        10-membered heterocyclyloxy, C₁-C₄-alkylcarbonyloxy and C₁-C₄        alkylthio; —(CHR¹³)_(n)-5- or 6-membered heteroaryl substituted        by 0 to 3 groups independently selected from the group        consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃,        OCF₃, and CF₂CH₃; —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, and CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl,        C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy,        di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR¹¹R¹², cyano, C₁-C₄ alkyl,        halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        C₃-C₆ cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,        C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,        (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴,        N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,        and a C₆-C₁₀ aryl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃,        OCF₃, and CF₂CH₃;    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        cyano, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, where halo is F or        Cl.    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   C₂-C₄ alkynyl,        -   —(CR¹⁴R¹⁴)_(n)-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n)—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n)-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   C₁-C₄-alkyleneoxy-C₁-C₄-alkylene,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   di-C₁-C₄-alkylaminophenyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        -   amino-C₁-C₄-alkylcarbonyl,        -   4- to 10-membered-heterocyclyl-carbonyl, and            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 10-membered mono- or            bicyclic heterocyclic ring containing carbon atoms            substituted by 0 to 3 groups independently selected from the            group consisting of halo, cyano, CF₃, CHF₂, OCF₃, OCHF₂,            OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,            hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to            2 additional heteroatoms selected from N, NR¹³, O and            S(O)_(p);    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to        10-membered heteroarylcarbonylamino) and —(CH₂)_(n)phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        cyano, oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, halo-C₁-C₄-alkyl, C₁-C₄-alkoxy, and        halo-C₁-C₄-alkoxy;    -   or R⁶ and R⁷ can be taken together with the carbons to which        they attach to form a C₆-C₁₀ aryl ring;    -   n, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I:

-   -   the dashed line represents an optional double-bond    -   X¹ is O and X² is CH, CR¹⁰, or N; or    -   X¹ is N and X² is O; or    -   X¹ is N, CH, or CR¹⁰, and X² is S; or    -   X¹ is N and X² is NH; or    -   X¹ is NH and X² is CH or CR¹⁰; or    -   X¹ is CH or CR¹⁰ and X² is NH;    -   X³, X⁴ and X⁵ are independently selected from CR³ or N;    -   W is O or S;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₂ alkoxy-C₁-C₂ alkyl,        -   tetrahydrofuran-2-yl;        -   C₁-C₄ alkylthio,        -   C₁-C₄ alkylNH—,        -   (C₁-C₄ alkyl)₂N—,        -   halo-C₁-C₂-alkyl, where halo is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R² is selected from the group consisting of:        -   H,        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy, and        -   halo-C₁-C₂-alkyl, where halo is F or Cl, and    -   cyano;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio,        halo, OH, CN, OCF₃, OCHF₂, OCH₂F, C₁-C₂-alkoxy-C₁-C₂-alkoxy,        halo-C₁-C₃-alkyl, benzyloxy substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, and        —(CH₂)_(n)-phenyl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        OCHF₂, di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁₋₄        hydroxyalkyl, C₁₋₄ fluoroalkyl or R⁴ and R⁵ can be taken        together with the carbon to which they are attached to form a        C₃-C₇ cycloalkyl ring;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one O, N or S atom, or a 6-memberedheteroaryl ring, containing at least one nitrogen atom;

-   -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, S(═O)₂NR¹¹R¹², and C₁-C₅        alkyl substituted by 0 to 7 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where    -   D is a linker, which is selected from a single bond, —O—, —S—,

C₁-C₄ alkylene substituted by 0 to 4 groups independently selected fromhalo or OH, C₁-C₄ alkyleneoxy, C₁-C₄ alkylenethio, C₁-C₄alkyleneoxy-C₁-C₄-alkylene, C₁-C₄-alkylenethio-C₁-C₄-alkylene,—S—C₁-C₄-alkylene, —O—C₁-C₄-alkylene, —NHC(═O)— and —C(═O)NH—, and C₂-C₆alkenylene,

-   -   B is selected from the group consisting of a C₆-C₁₀ aryl, a 5-        to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl        containing carbon atoms and 1 to 4 additional heteroatoms        selected from N, O, and S, a C₃-C₈ cycloalkyl which may contain        unsaturation and a C₅-C₁₁ spirocycloalkyl which may contain        unsaturation and optionally containing 1 to 3 heteroatoms        selected from O, N or S, all of which may be optionally        substituted with one or more R^(b), R^(c), R^(d) and R^(e);    -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from the group consisting of halo,        halo-C₁-C₄ alkoxy, OH, CN, NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy,        C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄        alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,        S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, SO₂R¹⁴,        N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹²,        O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₃-C₆ cycloalkyl, a 4- to        10-membered heterocyclyloxy; a C₁-C₅ alkyl substituted by 0 to 7        groups independently selected from halo, CF₃, OCF₃, OH, CN,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to        10-membered heterocyclyloxy, C₁-C₄-alkylcarbonyloxy and C₁-C₄        alkylthio; —(CHR¹³)_(n)-5- or 6-membered heteroaryl substituted        by 0 to 3 groups independently selected from the group        consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃,        OCF₃, and CF₂CH₃; —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, and CF₂CH₃;        di-C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆        cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,        C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, and a C₆-C₁₀ aryl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and        CF₂CH₃; R¹⁰ is selected from the group consisting of C₁-C₄        alkyl, halo, cyano, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, where        halo is F or Cl.

R¹¹ and R¹² are independently, at each occurrence, selected from thegroup consisting of:

-   -   H,    -   C₁-C₄ alkyl,    -   halo-C₁-C₄-alkyl,    -   C₂-C₄ alkenyl,    -   C₂-C₄ alkynyl,    -   —(CR¹⁴R¹⁴)_(n)-phenyl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        OCHF₂, di-C₁-C₄-alkylamino, and cyano,    -   —(CHR¹³)_(n)—C₃-C₆-cycloalkyl substituted by 0 to 3 groups        independently selected from the group consisting of halo, CF₃,        OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and        C₁-C₄ alkyl,    -   —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl substituted by 0 to        3 groups independently selected from the group consisting of        halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,        hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,    -   —(CHR¹³)_(n)-5- to 10-membered-heteroaryl substituted by 0 to 3        groups independently selected from the group consisting of halo,        CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl,        and C₁-C₄ alkyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,    -   C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,    -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   di-C₁-C₄-alkylaminophenyl,    -   hydroxy-C₁-C₄-alkyl,    -   cyano-C₁-C₄-alkyl,    -   C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,    -   C₁-C₄-alkoxycarbonyl,    -   C₁-C₄-alkylcarbonyl,    -   phenylcarbonyl;    -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,    -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,    -   amino-C₁-C₄-alkylcarbonyl,    -   4- to 10-membered-heterocyclyl-carbonyl, and    -   alternatively, R¹¹ and R¹², when attached to the same nitrogen,        combine to form a 4- to 10-membered mono- or bicyclic        heterocyclic ring containing carbon atoms substituted by 0 to 3        groups independently selected from the group consisting of halo,        cyano, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered        heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄        alkoxy, and 0 to 2 additional heteroatoms selected from N, NR¹³,        O and S(O)_(p);    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to        10-membered heteroarylcarbonylamino) and —(CH₂)_(n)phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        cyano, oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, halo-C₁-C₄-alkyl, C₁-C₄-alkoxy, and        halo-C₁-C₄-alkoxy    -   or R⁶ and R⁷ can be taken together with the carbons to which        they attach to form a C₆-C₁₀ aryl ring;    -   n, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I:

wherein:

-   -   the dotted line represents a single or double bond;        X¹ is O and X² is CH, CR¹⁰, or N; or    -   X¹ is N and X² is NH; or    -   X¹ is NH and X² is CH or CR¹⁰; or    -   X¹ is CH or CR¹⁰ and X² is NH;    -   X³, X⁴ and X⁵ are independently selected from CR³ or N;    -   W is O;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₂-C₃ alkenyl,        -   C₂-C₃ alkynyl,        -   C₃-C₄ cycloalkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₂ alkoxy-C₁-C₂ alkyl,        -   tetrahydrofuran-2-yl;        -   C₁-C₄ alkylthio,        -   C₁-C₄ alkylNH—,        -   (C₁-C₄ alkyl)₂N—,        -   halo-C₁-C₂-alkyl, where halo is F or Cl,        -   halo-C₃-C₄ cycloalkyl,        -   halo-C₁-C₂ alkoxy, and        -   halo-C₁-C₂ alkylthio;    -   R² is H;    -   R³ is selected from the group consisting of H, C₁-C₄ alkyl,        C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio,        halo, OH, CN, OCF₃, OCHF₂, OCH₂F, C₁-C₂-alkoxy-C₁-C₂-alkoxy,        halo-C₁-C₃-alkyl, benzyloxy substituted by 0 to 3 groups        independently selected from the group consisting of halo, C₁-C₄        alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered        heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, and        —(CH₂)_(n)-phenyl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,        OCHF₂, di-C₁-C₄-alkylamino, and cyano;    -   R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄        fluoroalkyl or R⁴ and R⁵ can be taken together with the carbon        to which they are attached to form a C₃-C₇ cycloalkyl ring;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one O, N or S atom, or a 6-memberedheteroaryl ring, containing at least one nitrogen atom;

-   -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, S(═O)₂NR¹¹R¹², and C₁-C₅        alkyl substituted by 0 to 7 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where    -   D is a linker, which is selected from a single bond, —O—, —S—,

C₁-C₄ alkylene substituted by 0 to 4 groups independently selected fromhalo or OH, C₁-C₄ alkyleneoxy, C₁-C₄ alkylenethio, C₁-C₄alkyleneoxy-C₁-C₄-alkylene, C₁-C₄-alkylenethio-C₁-C₄-alkylene,—S—C₁-C₄-alkylene, —O—C₁-C₄-alkylene, and C₂-C₆ alkenylene,

-   -   B is selected from the group consisting of a C₆-C₁₀ aryl, a 5-        to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl        containing carbon atoms and 1 to 4 additional heteroatoms        selected from N, O, and S, a C₃-C₈ cycloalkyl which may contain        unsaturation and a C₅-C₁₁ spirocycloalkyl which may contain        unsaturation and optionally containing 1 to 3 heteroatoms        selected from O, N or S, all of which may be optionally        substituted with one or more R^(b), R^(c), R^(d) and R^(e);    -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from the group consisting of halo,        halo-C₁-C₄ alkoxy, OH, CN, NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy,        C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄        alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,        S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, SO₂R¹⁴,        N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹²,        O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₃-C₆ cycloalkyl, a 4- to        10-membered heterocyclyloxy; a C₁-C₅ alkyl substituted by 0 to 7        groups independently selected from halo, CF₃, OCF₃, OH, CN,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to        10-membered heterocyclyloxy, C₁-C₄-alkylcarbonyloxy and C₁-C₄        alkylthio; —(CHR¹³)_(n)-5- or 6-membered heteroaryl substituted        by 0 to 3 groups independently selected from the group        consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃,        OCF₃, and CF₂CH₃; —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, and CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl,        C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy,        di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR¹¹R¹², cyano, C₁-C₄ alkyl,        halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        C₃-C₆ cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,        C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,        (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴,        N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,        and a C₆-C₁₀ aryl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃,        OCF₃, and CF₂CH₃;    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        cyano, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, where halo is F or        Cl.    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   C₂-C₄ alkynyl,        -   —(CR¹⁴R¹⁴)_(n)-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n)—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n)-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   di-C₁-C₄-alkylaminophenyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        -   amino-C₁-C₄-alkylcarbonyl,        -   4- to 10-membered-heterocyclyl-carbonyl, and            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 10-membered mono- or            bicyclic heterocyclic ring containing carbon atoms            substituted by 0 to 3 groups independently selected from the            group consisting of halo, cyano, CF₃, CHF₂, OCF₃, OCHF₂,            OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,            hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to            2 additional heteroatoms selected from N, NR¹³, O and            S(O)_(p);    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to        10-membered heteroarylcarbonylamino) and —(CH₂)_(n)phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        cyano, oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, halo-C₁-C₄-alkyl, C₁-C₄-alkoxy, and        halo-C₁-C₄-alkoxy    -   or R⁶ and R⁷ can be taken together with the carbons to which        they attach to form a C₆-C₁₀ aryl ring;    -   n, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I:

X¹ is O and X² is CH, CR¹⁰, or N; or

-   -   X¹ is N and X² is O; or    -   X¹ is N and X² is S;    -   X³, X⁴ and X⁵ are independently selected from CR³ or N;    -   W is O;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   C₁-C₄ alkylthio,        -   halo-C₁-C₂-alkyl, where halo is F or Cl,    -   R² is H;    -   R³ is selected from the group consisting of C₁-C₄ alkoxy, C₁-C₄        alkylthio, halo, OCF₃, OCHF₂, OCH₂F, or halo-C₁-C₃-alkyl;    -   R⁴ and R⁵ are independently selected from H, C₁-C₆ alkyl, C₁-C₄        fluoroalkyl or R⁴ and R⁵ can be taken together with the carbon        to which they are attached to form a C₃-C₇ cycloalkyl ring;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one O, N or S atom, or a 6-memberedheteroaryl ring, containing at least one nitrogen atom;

-   -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, S(═O)₂NR¹¹R¹², and C₁-C₅        alkyl substituted by 0 to 7 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where    -   D is a linker, which is selected from a single bond, —O—, —S—,

C₁-C₄ alkylene substituted by 0 to 4 groups independently selected fromhalo or OH, C₁-C₄ alkyleneoxy, C₁-C₄ alkylenethio, C₁-C₄alkyleneoxy-C₁-C₄-alkylene, C₁-C₄-alkylenethio-C₁-C₄-alkylene,—S—C₁-C₄-alkylene, —O—C₁-C₄-alkylene, and C₂-C₆ alkenylene,

-   -   B is selected from the group consisting of a C₆-C₁₀ aryl, a 5-        to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl        containing carbon atoms and 1 to 4 additional heteroatoms        selected from N, O, and S, a C₃-C₈ cycloalkyl which may contain        unsaturation and a C₅-C₁₁ spirocycloalkyl which may contain        unsaturation and optionally containing 1 to 3 heteroatoms        selected from O, N or S, all of which may be optionally        substituted with one or more R^(b), R^(c), R^(d) and R^(e);    -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from the group consisting of halo,        halo-C₁-C₄ alkoxy, OH, CN, NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy,        C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄        alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,        S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, SO₂R¹⁴,        N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹²,        O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₃-C₆ cycloalkyl, a 4- to        10-membered heterocyclyloxy; a C₁-C₅ alkyl substituted by 0 to 7        groups independently selected from halo, CF₃, OCF₃, OH, CN,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to        10-membered heterocyclyloxy, C₁-C₄-alkylcarbonyloxy and C₁-C₄        alkylthio; —(CHR¹³)_(n)-5- or 6-membered heteroaryl substituted        by 0 to 3 groups independently selected from the group        consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃,        OCF₃, and CF₂CH₃; —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, and CF₂CH₃;        di-C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆        cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,        C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, and a C₆-C₁₀ aryl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and        CF₂CH₃;    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        cyano, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, where halo is F or        Cl.    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   C₂-C₄ alkenyl,        -   C₂-C₄ alkynyl,        -   —(CR¹⁴R¹⁴)_(n)-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n)—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n)-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkyl,        -   C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,        -   di-C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   di-C₁-C₄-alkylaminophenyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl,        -   C₁-C₄-alkoxycarbonyl,        -   C₁-C₄-alkylcarbonyl,        -   phenylcarbonyl;        -   C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,        -   di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl,        -   amino-C₁-C₄-alkylcarbonyl,        -   4- to 10-membered-heterocyclyl-carbonyl, and            alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 10-membered mono- or            bicyclic heterocyclic ring containing carbon atoms            substituted by 0 to 3 groups independently selected from the            group consisting of halo, cyano, CF₃, CHF₂, OCF₃, OCHF₂,            OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,            hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to            2 additional heteroatoms selected from N, NR¹³, O and            S(O)_(p);    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino), (a 5- to        10-membered heteroarylcarbonylamino) and —(CH₂)_(n)phenyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,        di-C₁-C₄-alkylamino, and cyano,    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        cyano, oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl,        C₁-C₄-alkoxy-C₁-C₄-alkyl, halo-C₁-C₄-alkyl, C₁-C₄-alkoxy, and        halo-C₁-C₄-alkoxy    -   or R⁶ and R⁷ can be taken together with the carbons to which        they attach to form a C₆-C₁₀ aryl ring;    -   n, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I:

wherein:

-   -   the dotted line represents a single or double bond;        X is O and X² is CH, CR¹⁰, or N; or    -   X¹ is NH and X² is CH or CR¹⁰; or    -   X¹ is CH or CR¹⁰ and X² is NH;    -   X³, X⁴ and X⁵ are each CR³;    -   W is O;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy, and        -   halo-C₁-C₂-alkyl, where halo is F or Cl;    -   R² is H;    -   R³ is selected from the group consisting of H, C₁-C₄ alkoxyhalo,        OCF₃, OCHF₂, OCH₂F, and halo-C₁-C₃-alkyl;    -   R⁴ and R⁵ are independently selected from H, and C₁-C₆ alkyl;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one O, N or S atom, or a 6-memberedheteroaryl ring, containing at least one nitrogen atom;

-   -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, S(═O)₂NR¹¹R¹², and C₁-C₅        alkyl substituted by 0 to 7 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where    -   D is a linker, which is selected from a single bond, —O—, —S—,

C₁-C₄ alkylene, C₁-C₄ alkyleneoxy, C₁-C₄ alkylenethio, C₁-C₄alkyleneoxy-C₁-C₄-alkylene, C₁-C₄-alkylenethio-C₁-C₄-alkylene,—S—C₁-C₄-alkylene, —O—C₁-C₄-alkylene, —NHC(═O)—, —C(═O)NH—, and C₂-C₆alkenylene,

-   -   B is selected from the group consisting of a C₆-C₁₀ aryl, a 5-        to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl        containing carbon atoms and 1 to 4 additional heteroatoms        selected from N, O, and S, a C₃-C₈ cycloalkyl which may contain        unsaturation and a C₅-C₁₁ spirocycloalkyl which may contain        unsaturation and optionally containing 1 to 3 heteroatoms        selected from O, N or S, all of which may be optionally        substituted with one or more R^(b), R^(c), R^(d) and R^(e);    -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from the group consisting of halo,        halo-C₁-C₄ alkoxy, OH, CN, NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy,        C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄        alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,        S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, SO₂R¹⁴,        N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹²,        O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₃-C₆ cycloalkyl, a 4- to        10-membered heterocyclyloxy; a C₁-C₅ alkyl substituted by 0 to 7        groups independently selected from halo, CF₃, OCF₃, OH, CN,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to        10-membered heterocyclyloxy, C₁-C₄-alkylcarbonyloxy and C₁-C₄        alkylthio; —(CHR¹³)_(n)-5- or 6-membered heteroaryl substituted        by 0 to 3 groups independently selected from the group        consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃,        OCF₃, and CF₂CH₃; —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, and CF₂CH₃; OH, hydroxy-C₁-C₄-alkyl,        C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy,        di-C₁-C₄-alkylamino-C₁-C₄-alkyl, NR¹¹R¹², cyano, C₁-C₄ alkyl,        halo-C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        C₃-C₆ cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,        C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, COOR¹⁴, SO₂R¹⁴,        (C═O)NR¹¹R¹², SO₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴,        N(R¹³)(C═O)R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴,        and a C₆-C₁₀ aryl substituted by 0 to 3 groups independently        selected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄        alkyl, cyclopropyl, C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃,        OCF₃, and CF₂CH₃;    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        cyano, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, where halo is F or        Cl.    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl, and tetrahydrofuranyl;    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, and —(CH₂)_(n)phenyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or        6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and        cyano,    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        cyano, oxo, C₁-C₃ alkyl, hydroxy-C₁-C₃-alkyl, and        halo-C₁-C₄-alkyl;    -   or R⁶ and R⁷ can be taken together with the carbons to which        they attach to form a C₆-C₁₀ aryl ring;    -   n, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I:

X¹ is O and X² is CH or N; or

-   -   X¹ is N and X² is O; or    -   X¹ is N and X² is S;    -   X³, X⁴ and X⁵ are each CR³;    -   W is O;    -   R¹ is independently selected from the group consisting of:        -   halo,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy, and        -   halo-C₁-C₂-alkyl, where halo is F or Cl;    -   R² is H;    -   R³ is selected from the group consisting of H, C₁-C₄ alkoxy,        OCF₃, OCHF₂, OCH₂F, and halo-C₁-C₃-alkyl;    -   R⁴ and R⁵ are independently selected from H, and C₁-C₆ alkyl;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one O, N or S atom, or a 6-memberedheteroaryl ring, containing at least one nitrogen atom;

-   -   R⁶ is selected from the group consisting of H, halo, OCF₃,        OCHF₂, OH, CN, NO₂, NR¹¹R¹², COOH, C₁-C₄ alkoxycarbonyl,        (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, S(═O)₂NR¹¹R¹², and C₁-C₅        alkyl substituted by 0 to 7 groups independently selected from        halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄        alkoxy-C₁-C₄ alkoxy, di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or    -   R⁶ is B-D-, where    -   D is a linker, which is selected from a single bond, —O—, —S—,

C₁-C₄ alkylene, C₁-C₄ alkyleneoxy, C₁-C₄ alkylenethio, C₁-C₄alkyleneoxy-C₁-C₄-alkylene, C₁-C₄-alkylenethio-C₁-C₄-alkylene,—S—C₁-C₄-alkylene, —O—C₁-C₄-alkylene, —NHC(═O)—, —C(═O)NH—, and C₂-C₆alkenylene,

-   -   B is selected from the group consisting of a C₆-C₁₀ aryl, a 5-        to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl        containing carbon atoms and 1 to 4 additional heteroatoms        selected from N, O, and S, a C₃-C₈ cycloalkyl which may contain        unsaturation and a C₅-C₁₁ spirocycloalkyl which may contain        unsaturation and optionally containing 1 to 3 heteroatoms        selected from O, N or S, all of which may be optionally        substituted with one or more R^(b), R^(c), R^(d) and R^(e);    -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from the group consisting of halo,        halo-C₁-C₄ alkoxy, OH, CN, NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy,        C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄        alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl,        S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴, SO₂R¹⁴,        N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹²,        O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₃-C₆ cycloalkyl, a 4- to        10-membered heterocyclyloxy; a C₁-C₅ alkyl substituted by 0 to 7        groups independently selected from halo, CF₃, OCF₃, OH, CN,        hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,        di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,        (di-C₁-C₄-alkoxy-C₁-C₄-alkyl)C₁-C₄-alkyl, di-C₁-C₄-alkylamino,        C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to        10-membered heterocyclyloxy, C₁-C₄-alkylcarbonyloxy and C₁-C₄        alkylthio; —(CHR¹³)_(n)-5- or 6-membered heteroaryl substituted        by 0 to 3 groups independently selected from the group        consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃,        OCF₃, and CF₂CH₃; —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, CF₃, OCF₃, and CF₂CH₃;        di-C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆        cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀ arylcarbonyl,        C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, and a C₆-C₁₀ aryl        substituted by 0 to 3 groups independently selected from the        group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,        cyclopropyl, C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and        CF₂CH₃;    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        cyano, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, where halo is F or        Cl;    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl,        -   —(CR¹⁴R¹⁴)_(n)-phenyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or            6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and            cyano,        -   —(CHR¹³)_(n)—C₃-C₆-cycloalkyl substituted by 0 to 3 groups            independently selected from the group consisting of halo,            CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n)-4- to 10-membered-heterocyclyl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, oxo,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   —(CHR¹³)_(n)-5- to 10-membered-heteroaryl substituted by 0            to 3 groups independently selected from the group consisting            of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,            hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,        -   hydroxy-C₁-C₄-alkyl,        -   cyano-C₁-C₄-alkyl,        -   C₁-C₄-alkoxy-C₁-C₄-alkyl, and        -   alternatively, R¹¹ and R¹², when attached to the same            nitrogen, combine to form a 4- to 10-membered mono- or            bicyclic heterocyclic ring containing carbon atoms            substituted by 0 to 3 groups independently selected from the            group consisting of halo, cyano, CF₃, CHF₂, OCF₃, OCHF₂,            OCH₂F, 5- or 6-membered heteroaryl, OH, oxo,            hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to            2 additional heteroatoms selected from N, NR¹³, O and            S(O)_(p);    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,        C₁-C₄-alkoxycarbonylamino, and —(CH₂)_(n)phenyl substituted by 0        to 3 groups independently selected from the group consisting of        halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or        6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and        cyano,    -   R⁷ is selected from the group consisting of H, halo, hydroxyl,        cyano, oxo, C₁-C₃ alkyl, hydroxy-C₁-C₃-alkyl, and        halo-C₁-C₄-alkyl;    -   or R⁶ and R⁷ can be taken together with the carbons to which        they attach to form a C₆-C₁₀ aryl ring;    -   n, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I:

wherein

-   -   the dotted line represents a single or double bond;        X¹ is O and X² is CH;    -   X³, and X⁵ are each CH, and X⁴ is CR³;    -   W is O;    -   R¹ is independently selected from the group consisting of: H,        CH₃, and OCH₃;    -   R² is H;    -   R³ is selected from the group consisting of H, and OCH₃;    -   R⁴ and R⁵ are H;

is selected from the group consisting of a phenyl, pyrimidinyl, andthiazolyl; R⁶ is phenyl, morpholinyl, piperidinyl, all of which may beoptionally substituted with one or more R^(b), R^(c), R^(d) and R^(e);

-   -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from OH, (C═O)NRR¹², COOH, (C═O)OR¹⁴,    -   R¹⁰ is selected from the group consisting of C₁-C₄ alkyl, halo,        cyano, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, where halo is F or        Cl.    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:        -   H,        -   C₁-C₄ alkyl,        -   halo-C₁-C₄-alkyl, and tetrahydrofuranyl;    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, and CH₃;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, and CH₃; R⁷ is selected from the group        consisting of H, or CH₃;    -   n, at each occurrence, is selected from 0, 1, or 2; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I:

-   -   X¹ is O and X² is CH;    -   X³, and X⁵ are each CH, and X⁴ is CR³;    -   W is O;    -   R¹ is independently selected from the group consisting of: CH₃,        CH₂CH₃, CF₂CH₃, CHFCH₃, and OCH₃;    -   R² is H;    -   R³ is OCH₃;    -   R⁴ and R⁵ are H;

is selected from the group consisting of phenyl, pyridyl, pyrimidinyl,pyrazinyl, and thiazolyl;

-   -   R⁶ is selected from the group consisting of phenyl, cyclopentyl,        cyclohexyl, pyridyl, morpholinyl, thiomorpholinyl, azetidinyl,        pyrrolidinyl, piperidinyl, piperazinyl, azepanyl,        tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, oxazolyl,        isoxazolyl, pyrazolyl, and imidazolyl, all of which may be        optionally substituted with one or more R^(b), R^(c), R^(d) and        R^(e);    -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from halo, halo-C₁-C₄ alkoxy, OH, CN,        NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄        alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl, C₁-C₄        alkylsulfinyl, S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,        N(R¹³)(C═O)OR¹⁴, SO₂R¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴,        NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, and        a C₁-C₅ alkyl substituted by 0 to 7 groups independently        selected from halo and OH;    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of:    -   H,    -   C₁-C₄ alkyl,    -   halo-C₁-C₄-alkyl,    -   cyclopropyl,    -   cyclopropylmethyl    -   hydroxy-C₁-C₄-alkyl,    -   cyano-C₁-C₄-alkyl,    -   C₁-C₄-alkoxy-C₁-C₄-alkyl,    -   oxetanyl,    -   tetrahydrofuranyl, and    -   alternatively, R¹¹ and R¹², when attached to the same nitrogen,        combine to form an azetidine, pyrrolidine, piperidine, or        azepane ring, substituted by 0 to 2 groups independently        selected from the group consisting of halo, cyano, CF₃, CHF₂,        OCF₃, OCHF₂, OCH₂F, OH, oxo, C₁-C₄ alkyl and C₁-C₄ alkoxy;    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, and CH₃;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, and CH₃; R⁷ is selected from the group        consisting of H, F, or CH₃;    -   n, at each occurrence, is selected from 0, 1, or 2; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, wherein Wis O.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, ofFormula Ia.

In another embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, ofFormula I, or Ia,

wherein R¹ is C₁₋₃alkyl;

W is O;

X⁴ is CR³ or CH;

R³ is C₁-C₄ alkoxy;

R⁴ and R⁵ are H;

is phenyl or thiazolyl, wherein the thiazolyl is substituted with R⁶;

-   -   R⁶ is H or B-D:    -   D is a single bond;    -   B is phenyl which may be optionally substituted with R^(b);    -   R^(b) is (C═O)NR¹¹R¹²;        -   R¹¹ and R¹² are independently, at each occurrence, selected            from the group consisting of:            -   H,            -   C₁-C₄ alkyl.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein:

-   -   the dashed line represents an optional double-bond;    -   X is CR^(1a) or N;    -   Y is CR^(1a) or N;    -   Z is CR^(1a) or N;    -   provided that at least one of X, Y, and Z is N, and provided        that if X is N, then at least one of Y and Z is N;        X¹ is O and X² is CH;    -   X³, and X⁵ are CH, and X⁴ is CR³;    -   W is O;    -   R¹ is independently selected from the group consisting of: H,        CH₃, and OCH₃;    -   R^(1a) is selected from the group consisting of H, halo, C₁-C₄        alkyl, and C₁-C₄ alkoxy;    -   R² is H;    -   R³ is selected from the group consisting of H, and OCH₃;    -   R⁴ and R⁵ are H;

is selected from the group consisting of phenyl, pyrimidinyl, andthiazolyl;

-   -   R⁶ is phenyl, morpholinyl, piperidinyl, all of which may be        optionally substituted with one or more R^(b), R^(c), R^(d) and        R^(e);    -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from OH, (C═O)NR¹¹R¹², COOH, (C═O)OR¹⁴,    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of H; C₁-C₄ alkyl, halo-C₁-C₄-alkyl, and        tetrahydrofuranyl; or    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, and CH₃;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, and CH₃,    -   R⁷ is selected from the group consisting of H, or CH₃;    -   n, at each occurrence, is selected from 0, 1, or 2; and    -   p, at each occurrence, is selected from 0, 1 and 2.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   X¹ is O and X² is CH, CR¹⁰, or N; or    -   X¹ is N and X² is NH; or    -   X¹ is NH and X² is CH or CR¹⁰; or    -   X¹ is CH or CR¹⁰ and X² is NH;    -   X³, X⁴ and X⁵ are independently selected from CR³ or N;    -   W is O.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   X¹ is O and X² is CH, CR¹⁰, or N; or    -   X¹ is NH and X² is CH or CR¹⁰; or    -   X¹ is CH or CR¹⁰ and X² is NH;    -   in ring A, X³, X⁴ and X⁵ are independently selected from CR³; W        is O.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   X¹ is O and X² is CH;    -   in ring A, X³ and X⁵ are CH, and X⁴ is CR³;    -   W is O.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   R² is H.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   R¹ is independently selected from the group consisting of: H,        CH₃, and OCH₃.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   R¹ is independently selected from the group consisting of: CH₃        and CH₂CH₃.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   in ring A, X³, and X⁵ are CH, and X⁴ is CR³; and    -   R³ is selected from the group consisting of H, and OCH₃.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   R⁴ and R⁵ are H.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

is selected from the group consisting of phenyl, pyrimidinyl, andthiazolyl; R⁶ is phenyl, morpholinyl, piperidinyl, all of which may beoptionally substituted with one or more R^(b), R^(c), R^(d) and R^(e);

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from OH, (C═O)NR¹¹R¹², COOH, (C═O)OR¹⁴,    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of H; C₁-C₄ alkyl, halo-C₁-C₄-alkyl, and        tetrahydrofuranyl; or    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, and CH₃;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, and CH₃, and    -   R⁷ is selected from the group consisting of H, or CH₃.

In still yet another embodiment, the present invention providescompounds, stereoisomers, tautomers, salts, solvates or prodrugsthereof, wherein the compounds are compounds of Formula I, or they arecompounds of Formula Ia:

-   -   R^(b), R^(c), R^(d) and R^(e), at each occurrence, are        independently selected from OH, fluoro, chloro, (C═O)NR¹¹R¹²,        COOH, and (C═O)OR¹⁴;    -   R¹¹ and R¹² are independently, at each occurrence, selected from        the group consisting of H; C₁-C₄ alkyl, halo-C₁-C₄-alkyl,        hydroxy-C₁-C₄-alkyl, oxetanyl, and tetrahydrofuranyl; or    -   R¹³ is independently, at each occurrence, selected from the        group consisting of H, and CH₃;    -   R¹⁴ is independently, at each occurrence, selected from the        group consisting of H, and CH₃, and    -   R⁷ is selected from the group consisting of H, F, or CH₃.

In one embodiment, the present invention provides compounds,stereoisomers, tautomers, salts, solvates or prodrugs thereof, whereinthe compounds are compounds of Formula I or Ia.

PAR4 compounds of the invention have IC₅₀s in the FLIPR Assay (describedhereinafter) of about 10 μM, or 5 μM or less, or 500 nM or less, or 10nM or less. Activity data for Examples 1-4 is described in Example E.

In some embodiments, the present invention provides at least onecompound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate, or prodrug ester thereof.

In some embodiments, the present invention provides a pharmaceuticalcomposition, which includes a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of Formula I, or Ia,preferably, a compound selected from one of the examples, morepreferably, Examples 1 to 4, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,alone or in combination with another therapeutic agent.

In some embodiments, the present invention provides a pharmaceuticalcomposition which further includes another therapeutic agent(s). In apreferred embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are P2Y12 antagonists and/or aspirin. Preferably,the P2Y12 antagonists are clopidogrel, ticagrelor, or prasugrel. Inanother preferred embodiment, the present invention provides apharmaceutical composition, wherein the additional therapeutic agent(s)are an anticoagulant or a combination thereof. Preferably, theanticoagulant agent(s) are FXa inhibitors or thrombin inhibitors.Preferably, the FXa inhibitors are apixaban or rivaroxaban. Preferably,the thrombin inhibitor is dabigatran.

In some embodiments, the present invention provides a method for thetreatment or prophylaxis of a thromboembolic disorder which includes thestep of administering to a subject (for example, a human) in need ofsuch treatment or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugs, orestersthereof.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, or Ia,preferably, a compound selected from one of the examples, morepreferably, Examples 1 to 4, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, cerebrovascular thromboembolicdisorders, and thromboembolic disorders in the chambers of the heart orin the peripheral circulation.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I or Ia,preferably, a compound selected from one of the examples, morepreferably, Examples 1 to 4, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of acute coronary syndrome, unstable angina, stable angina,ST-elevated myocardial infarction, non-ST-elevated myocardialinfarction, atrial fibrillation, myocardial infarction, transientischemic attack, stroke, atherosclerosis, peripheral arterial disease,venous thrombosis, deep vein thrombosis, thrombophlebitis, arterialembolism, coronary arterial thrombosis, cerebral arterial thrombosis,cerebral embolism, kidney embolism, pulmonary embolism, cancer-relatedthrombosis, and thrombosis resulting from medical implants, devices, andprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, or Ia,preferably, a compound selected from one of the examples, morepreferably, Examples 1 to 4, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of acute coronary syndrome, unstable angina, stable angina,ST-elevated myocardial infarction, and non-ST-elevated myocardialinfarction.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula Ior Ia,preferably, a compound selected from one of the examples, morepreferably, Examples 1 to 4, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of transient ischemic attack and stroke.

In some embodiments, the present invention provides methods for thetreatment of a thromboembolic disorder or the primary or secondaryprophylaxis of a thromboembolic disorder, which includes the steps ofadministering to a patient (for example, a human) in need thereof atherapeutically effective amount of a compound of Formula I, or Ia,preferably, a compound selected from one of the examples, morepreferably, Examples 1 to 4, or stereoisomers, tautomers,pharmaceutically acceptable salts, prodrug esters, or solvates thereof,wherein the thromboembolic disorder is peripheral arterial disease.

In some embodiments, the present invention includes a method asdescribed above wherein the thromboembolic disorder is selected fromunstable angina, an acute coronary syndrome, atrial fibrillation, firstmyocardial infarction, recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, peripheralocclusive arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis.

In some embodiments, the present invention includes a method ofinhibiting or preventing platelet aggregation, which includes the stepof administering to a subject (such as a human) in need thereof atherapeutically effective amount of a PAR4 antagonist, which is acompound of Formula Ior Ia, preferably, a compound selected from one ofthe examples, more preferably, Examples 1 to 4, of the invention.

Other Embodiments of the Invention

In some embodiments, the present invention provides a process for makinga compound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug ester thereof.

In some embodiments, the present invention provides an intermediate formaking a compound of the present invention or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug ester thereof.

In some embodiments, the invention provides a method of treatment orprophylaxis of a thromboembolic disorder involving administering to asubject in need thereof (e.g., a human) a therapeutically effectiveamount of a compound that binds to PAR4 (such as a compound of Formula Iof the invention) and inhibits PAR4 cleavage and/or signaling, whereinsaid subject has a dual PAR1/PAR4 platelet receptor repertoire.

In some embodiments, the present invention provides a compound of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs, or estersthereof, for use intherapy for the treatment or prophylaxis of a thromboembolic disorder.

In some embodiments, the present invention also provides the use of acompound of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs, or estersthereof, for the manufacture of a medicament for the treatment orprophylaxis of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

Chemistry

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis- andtrans-geometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated. When nospecific mention is made of the configuration (cis, trans or R or S) ofa compound (or of an asymmetric carbon), then any one of the isomers ora mixture of more than one isomer is intended. The processes forpreparation can use racemates, enantiomers, or diastereomers as startingmaterials. All processes used to prepare compounds of the presentinvention and intermediates made therein are considered to be part ofthe present invention. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods, for example, bychromatography or fractional crystallization. Compounds of the presentinvention, and salts thereof, may exist in multiple tautomeric forms, inwhich hydrogen atoms are transposed to other parts of the molecules andthe chemical bonds between the atoms of the molecules are consequentlyrearranged. It should be understood that all tautomeric forms, insofaras they may exist, are included within the invention.

As used herein, the term “alkyl” or “alkylene”, alone or as part ofanother group, is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having from 1 to 10 carbons orthe specified number of carbon atoms. For example, “C₁₋₁₀ alkyl” (oralkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉,and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl” denotesalkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted orsubstituted with at least one hydrogen being replaced by anotherchemical group. Example alkyl groups include, but are not limited to,methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl(e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl,isopentyl, neopentyl), as well as chain isomers thereof.

“Alkenyl” or “alkenylene”, alone or as part of another group, isintended to include hydrocarbon chains of either straight or branchedconfiguration and having one or more carbon-carbon double bonds that mayoccur in any stable point along the chain. For example, “C₂₋₆ alkenyl”(or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenylgroups. Examples of alkenyl include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, and 4-methyl-3-pentenyl, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonyl-amino, nitro, cyano, thiol, and/or alkylthio.

“Alkynyl” or “alkynylene”, alone or as part of another group, isintended to include hydrocarbon chains of either straight or branchedconfiguration and having one or more carbon-carbon triple bonds that mayoccur in any stable point along the chain. For example, “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy”, alone or as part of another group,refers to an —O-alkyl group, where alkyl is as defined above. “C₁₋₆alkoxy” (or alkyloxy), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆alkoxy groups. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.Similarly, “alkylthio” or “thioalkoxy”, alone or as part of anothergroup, represents an alkyl group or alkoxy group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example methyl-S— and ethyl-S—.

“Halo” or “halogen”, alone or as part of another group, includes fluoro,chloro, bromo, and iodo.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with at least one halogen, up to fullysubstituted with halogens (perhaloalkyl), alternatively 1 to 7halogensor 1 to 4 halogens, preferably F and/or Cl. Examples ofhaloalkyl include, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,1,1-difluoroethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl,heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl alsoinclude “fluoroalkyl” that is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 to 7 fluorineatoms, preferably 1 to 4 fluorine atoms.

“Halo-C₁-C₂-alkoxy” or “haloalkyloxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly,“haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (orbicycloalkyl), and tricyclic alkyl, containing a total of 3 to 10carbons forming the ring (C₃-C₁₀ cycloalkyl), and which may be fused to1 or 2 aromatic rings as described for aryl, which includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, cyclododecyl, cyclohexenyl, norbomyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/orany of the substituents for alkyl, as well as such groups including 2free bonds and thus are linking groups.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring,any of which may be saturated, partially unsaturated, unsaturated oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, andtetrahydronaphthyl (tetralin). As shown above, bridged rings are alsoincluded in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).Preferred carbocycles, unless otherwise specified, are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term“carbocycle” is used, it is intended to include “aryl”. A bridged ringoccurs when one or more carbon atoms link two non-adjacent carbon atoms.Preferred bridges are one or two carbon atoms. It is noted that a bridgealways converts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.Unless otherwise specified, “aryl”, “C₆₋₁₀ aryl” or “aromatic residue”may be unsubstituted or substituted with 1 to 3 groups selected from OH,C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃,OCHF₂, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₃ alkyl, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle”, “heterocyclo” or “heterocyclic”group is intended to mean a stable 4- to 14-membered monocyclic,bicyclic or tricyclic heterocyclic ring which is saturated or partiallyunsaturated and which consists of carbon atoms and 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, NH, Oand S and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may optionally be substituted on carbon or on anitrogen atom if the resulting compound is stable, with 1 to 3 groupsselected from OH, OC₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H,N(CH₃)₂, CF₃, OCF₃, OCHF₂, =0, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃,C₁-C₃ alkyl, CO₂H and CO₂CH₃. The heterocycle may optionally contain a═O. A nitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. Spiro and bridged rings are also included in thedefinition ofheterocycle. A bridged ring occurs when one or more atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.When the term “heterocycle” is used, it is not intended to includeheteroaryl.

Exemplary monocyclic heterocyclic groups include azetidinyl,pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, and the like.

Exemplary bicyclic heterocyclo groups include quinuclidinyl.

Heterocyclo groups include

which optionally may be substituted.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are unsubstitutedor substituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2). Bridged rings are also included inthe definition of heteroaryl. A bridged ring occurs when one or moreatoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogenatoms. Examples of bridged rings include, but are not limited to, onecarbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms,and a carbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

Heteroaryl groups include, but are not limited to,

-   -   and the like.

When the term “unsaturated” is used herein to refer to a ring or group,which group may be fully unsaturated or partially unsaturated.

The term “acyl” alone or as part of another group refers to a carbonylgroup linked to an organic radical, more particularly, the groupC(═O)R_(e), as well as the bivalent groups —C(═O)— or —C(═O)R_(e)—,which are linked to organic radicals. The group R_(e) can be selectedfrom alkyl, alkenyl, alkynyl, aminoalkyl, substituted alkyl, substitutedalkenyl, or substituted alkynyl, as defined herein, or when appropriate,the corresponding bivalent group, e.g., alkylene, alkenylene, and thelike.

The designation “

” or “

” or “

” attached to a ring or other group refers to a free bond or linkinggroup.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative. In cases in which there are quaternary carbonatoms in compounds of the present invention, these can be replaced bysilicon atoms, provided they do not form Si—N or Si—O bonds.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0 to 3 R^(3a), then said group mayoptionally be substituted with up to three R^(3a) groups, and at eachoccurrence R^(3a) is selected independently from the definition ofR^(3a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, L. V., Jr.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,    Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and    Development, pp. 113-191, Harwood Academic Publishers (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and-   f) Rautio, J (Editor). Prodrugs and Targeted Delivery (Methods and    Principles in Medicinal Chemistry), Vol 47, Wiley-VCH, 2011.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced(2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism.Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich,Switzerland (2003); Wermuth, C. G., ed., The Practice of MedicinalChemistry, 3rd Edition, Academic Press, San Diego, Calif. (2008).

Isotopically labeled compounds of the present invention, i.e., whereinone or more of the atoms described are replaced by an isotope of thatatom (e.g., ¹²C replaced by ¹³C or by ¹⁴C; and isotopes of hydrogenincluding tritium and deuterium), are also provided herein. Suchcompounds have a variety of potential uses, e.g., as standards andreagents in determining the ability of a potential pharmaceuticalcompound to bind to target proteins or receptors, or for imagingcompounds of this invention bound to biological receptors in vivo or invitro.

Compounds of the present invention are, subsequent to their preparation,preferably isolated and purified to obtain a composition containing anamount by weight equal to or greater than 98%, preferably 99%, compoundof the present invention (“substantially pure”), which is then used orformulated as described herein. Such “substantially pure” compounds arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates include, butare not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight,“mp” for melting point, “MS” or “Mass Spec” for mass spectrometry, “ESI”for electrospray ionization mass spectroscopy, “HR” for high resolution,“HRMS” for high resolution mass spectrometry, “LCMS” for liquidchromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” for thin layerchromatography, “SM” for starting material, “NMR” for nuclear magneticresonance spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “tlc” for thin layer chromatography.“α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designationsfamiliar to one skilled in the art.

Me methyl Et ethyl Pr propyl i-Pr isopropyl Bu butyl i-Bu isobutyl t-Butert-butyl Ph phenyl Bn benzyl AcOH acetic acid MeOH methanol EtOHethanol EtOAc ethyl acetate Et2O diethyl ether i-PrOH or IPA isopropanolHOAc acetic acid BOP reagent benzotriazol-1-yloxytris(diethylamino)phosphonium hexafluorophosphate BBr₃ borontribromide Boc tert-butyloxycarbonyl cDNA complimentary DNA CDCl₃deuterated chloroform CH₂Cl₂ dichloromethane CH₃CN acetonitrile ACNacetonitrile DABCO 1,4-diazabicyclo[2.2.2]octane DCE 1,2 dichloroethaneDCM dichloromethane DCC dicyclohexylcarbodiimide DIAD diisopropylazodicarboxylate DIEA or DIPEA N,N-diisopropylethylamine DME1,2-dimethoxyethane DMF dimethyl formamide DMAPN,N-dimethylaminopyridine DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide EDC (or EDC.HCl) or3-ethyl-3′-(dimethylamino)propyl-carbodiimide EDCI (or EDCI.HCl) orhydrochloride EDAC or 1-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride EDTA ethylenediaminetetraacetic acid HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HCl hydrochloric acid HEPES4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid Hex hexane HOBt orHOBT 1-hydroxybenzotriazole monohydrate Hunig's baseN,N-diisopropylethyl amine LAH lithium aluminum hydride LDA Lithiumdiisopropylamide LiHMDS Lithium bis(trimethylsilyl) amide mCPBA orm-CPBA meta-chloroperbenzoic acid NMM N-methylmorpholine Pd/C palladiumon carbon PPA polyphosphoric acid PS polystyrene PXPd2 bis[di-tert-butylphosphinous chloride-kP]di-m- chlorodichloro dipalladium PyBOP(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate TEAtriethylamine TFA trifluoroacetic acid THF tetrahydrofuran TRIStris(hydroxymethyl)aminomethane KOAc potassium acetate K₃PO₄ potassiumphosphate MgSO₄ magnesium sulfate NaCl sodium chloride NaH sodiumhydride NaHCO₃ sodium bicarbonate NaOH sodium hydroxide Na₂SO₃ sodiumsulfite Na₂SO₄ sodium sulfate NH₃ ammonia NH₄Cl ammonium chloride NH₄OHammonium hydroxide OTs tosylate, para-toluenesulfonate PBr₃ phosphoroustribromide Pd(PPh₃)₄ tetrakis(triphenylphosphine) palladium (0)(S,S)-EtDuPhosRh(I) (+)-1,2-bis((2S,5S)-2,5- diethylphospholano)benzene(cyclooctadiene)rhodium (I) trifluoromethanesulfonate

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Wuts et al. (Greene's Protective Groups In OrganicSynthesis, 4th Edition, Wiley-Interscience (2006)).

Compounds of formula 3 of this invention can be obtained by condensationof an amine of formula 1 with a ketone of formula 2 which contains aleaving group X such as a bromide, chloride, iodide or tosylate and aprotecting group PG such as benzyl as shown in Scheme 1. Both compoundsof formula 1 and 2 are commercially available or can be prepared bymeans known to one skilled in the art. This condensation is promoted byheating, either thermally or preferably by microwave irradiation. Theprotecting group can be removed by methods known in the art, such asBCl₃ at −78° C. in the presence of pentamethylbenzene. Subsequentalkylation using either an alcohol 4 under Mitsunobu conditions or abromide 5 in the presence of base such as cesium carbonate provides thecompounds of Formula 6. Alcohols 4 and bromides 5 are commerciallyavailable or can be prepared by methods known in the art.

In the event that the condensation of an amine of formula 1 with aketone of formula 2 does not proceed to compounds of Formula 3 in asingle step, compounds of Formula 3 can be prepared from dehydration ofcompounds of Formula 8 with POCl₃, as shown in Scheme 2. Compounds offormula 8 can be prepared from the hydrolysis of compounds of Formula 7,which in turn can be derived from the reaction of an amine of formula 1with a ketone of formula 2. Compounds 3 can be converted to compounds ofFormula 6 by removal of the protecting group (PG) and alkylation asdiscussed in Scheme 1.

In addition, the PCT publications WO2013/163279, WO2013/163244, andWO2013/163241 disclose synthesis of many reagents of structure 4 and 5containing ring AA (shown in Schemes 1 and 2) which are useful forpreparing compounds of this invention.

Aminooxadiazoles 1 may be commerically available or can be prepared bereacting hydrazides 9 with cyanogen bromide 10, by heating in, forinstance, an alcoholic solvent such as methanol, or treating with a basesuch as sodium bicarbonate or sodium acetate in, for instance, a mixtureof water and dioxane. Addition of bromine or iodine may facilitate thereaction.

Substituted benzofurans 14, bearing α-bromoketone substituents at the2-position, can be prepared as shown in Scheme 4. o-Hydroxybenzaldehydes 11 can be prepared by methods known to one skilled in theart of organic synthesis, and can be condensed with ketones of formula12, bearing a leaving group Q such as chloro, bromo or tosyloxy, to givebenzofurans 13. Bromination of compounds of formula 13 affordsbromoketones 14, which can be condensed with substitutedaminooxadiazoles 1 according to Scheme 1 or 2 to give compounds ofFormula I. Bromoketones 14 are a specific subset of compounds 2 inSchemes 1 and 2.

Benzoxazole compounds of Formula I can be prepared starting fromsubstituted aminooxadiazoles 1 and pyruvate esters of formula 15 whichcontain a leaving group Q such as a bromide, iodide or tosylate as shownin Scheme 5. Both compounds of formula 1 and 14 are commerciallyavailable or are available by means known to one skilled in the art.Following condensation and saponification of the esters 16 to form acids17, amino phenols of formula 18 or 19 are coupled to form amides offormula 20 or 21, which can be cyclized under acid catalysis to formbenzoxazole compounds of formula 22 or 23. These can be deprotected andalkylated as shown in Scheme 1 to provide compounds of Formula I.

Benzothiazole compounds of the invention can be prepared fromintermediates described in Scheme 6. Reaction of bromo anilines 24,which are commercially available or can be prepared by one skilled inthe art, with benzoylisothiocyanate affords thioureas 26, which arehydrolyzed with NaOH and heat to afford thioureas 27. These thioureascan be oxidatively cyclized with, for instance, bromine in a solventsuch as chloroform, to give aminobenzothiazoles 28. Reaction with anorganic nitrite provides benzothiazoles 29. Subsequent deprotonation andreaction with a Weinreb amide gives acylbenzothiazoles 30. Theseintermediates can be brominated, with for instance,phenyltrimethylammonium tribromide, to give bromoketones 31. Theseintemediates can be converted to compounds of the invention usingchemistry shown in Scheme 1, followed by derivitization of the arylbromide using methods known to one skilled in the art.

Benzothiazole compounds of the invention can also be prepared withintermediates shown in Scheme 7. Bromobenzothiazoles 29, prepared asshown in Scheme 6, can be converted to a boronate and oxidized tophenols 32. Reaction with a protecting group containing a reactivehalogen, such as benzyl bromide, in the presence of base, such aspotassium carbonate, affords protected benzothiazoles 33. Acylation ofthe benzothiazole 2-position using a Weinreb amide and strong base, andsubsequent bromination gives bromoketones 35, which can be converted tocompounds of Formula I as shown in Scheme 1.

General Methods

The following methods were used in the exemplified Examples, exceptwhere noted otherwise.

Products were analyzed by reverse phase analytical HPLC carried out on aShimadzu Analytical HPLC system running Discovery VP software using oneof the following methods:

Method A: PHENOMENEX® Luna C18 column (4.6×50 mm or 4.6×75 mm) eluted at4 mL/min with a 2, 4 or 8 min gradient from 100% A to 100% B (A: 10%methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA,UV 220 nm).

Method B: PHENOMENEX® Luna C18 column (4.6×50 mm) eluted at 4 mL/minwith a 2, 4 or 8 min gradient from 100% A to 100% B (A: 10%acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile,0.1% TFA, UV 220 nm).

Reverse phase preparative HPLC was carried out using a ShimadzuPreparative HPLC system running Discovery VP software using one of thefollowing methods.

Method A: PHENOMENEX® Axia Luna 5 μm C18 30×75 mm column with a 10 mingradient at 40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9%water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).

Method B: XBridge C18, 19×200 mm column, 5-am particles; Mobile Phase A:5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B:95:5 acetonitrile: water with 0.1% trifluoroaceticacid; Flow: 20 mL/min.

LCMS chromatograms were obtained on a Shimadzu HPLC system runningDiscovery VP software, coupled with a Waters ZQ mass spectrometerrunning MassLynx version 3.5 software using a linear gradient usingsolvent A (10% acetonitrile, 90% water, 0.1% of TFA) and solvent B (90%acetonitrile, 10% water, 0.1% of TFA); Column: BEH C18 2.1×50 mm;wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 2 to 98%B.

In addition, the following orthogonal HPLC conditions were used to checkthe purity of the compounds:

Method A: Two analytical LC/MS injections were used to determine thefinal purity. Injectionl condition: A linear gradient using solvent A(5% acetonitrile, 95% water, 0.05% TFA) and solvent B (95% acetonitrile,5% water, 0.05% TFA); 10-100% of solvent B over 10 min and then 100% ofsolvent B over 5 min. Column: Sunfire C18 3.5 um (4.6×150 mm). Flow ratewas 2 ml/min. and UV detection was set to 220 nm. The LC column wasmaintained at room temperature. Injection 2 conditions: A lineargradient using solvent A (5% acetonitrile, 95% water, 0.05% TFA) andsolvent B (95% acetonitrile, 5% water, 0.05% TFA); 10-100% of solvent Bover 10 min and then 100% of solvent B over 5 min. Column: XbridgePhenyl 3.5 um (4.6×150 mm). Flow rate was 2 ml/min. and UV detection wasset to 220 nm. The LC column was maintained at room temperature.

Method B: Two analytical LC/MS injections were used to determine thefinal purity. Injection 1 conditions: Column: Waters Acquity UPLC BEHC18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B;Flow: 1.11 mL/min; Detection: UV at 220 nm. Injection 2 conditions:Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

EXAMPLES

The following Examples have been prepared, isolated and characterizedusing the methods disclosed herein. The following examples are not meantto be limiting of the scope of the invention.

Example 16-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-ethylimidazo[2,1-b][1,3,4]oxadiazole

Example 1A1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-(5-ethyl-2-imino-1,3,4-oxadiazol-3(2H)-yl)ethanonehydrobromide

A suspension of 5-ethyl-1,3,4-oxadiazol-2-amine (139 mg, 1.231 mmol) and1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (385 mg,1.026 mmol, for preparation, see PCT Int. Appl. (2013), WO 2013163241)in isopropanol (6 mL) was heated in a sealed vial at 75° C. Thesuspension turned to a clear solution. The reaction mixture was keptstirring at 75° C. overnight. Precipitate formed at the end of thereaction. The reaction mixture was triturated with diethyl ether. Theprecipitate was collected by filtration, washed with diethyl ether anddried under vacuum to give Example 1A (404 mg, 0.827 mmol, 81% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 1H), 7.58-7.52 (m,2H), 7.48-7.43 (m, 2H), 7.41-7.37 (m, 1H), 6.99 (s, 1H), 6.67 (d, J=1.8Hz, 1H), 5.67 (s, 2H), 5.31 (s, 2H), 3.87 (s, 3H), 2.88 (q, J=7.5 Hz,2H), 1.24 (t, J=7.5 Hz, 3H); LC-MS: RT=0.75 min, MS (ESI) m/z: 408.1(M+H)

Example 1BN-(4-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)propionamide

To a solution of Example 1A (404 mg, 0.827 mmol) in water (6 mL) and THF(3 mL) was added 1.0 N NaOH (1.075 mL, 1.075 mmol). The reaction mixturewas heated at 60° C. for 2.0 h. LCMS indicated a clean reaction. Thereaction mixture was diluted with EtOAc/0.5 N HCl. The organic layer waswashed with brine, dried over sodium sulfate and concentrated to giveExample 1B (337 mg, 0.827 mmol, 100% yield) as a brown solid. It wasused for the next step without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 10.91 (d, J=2.0 Hz, 1H), 10.61 (s, 1H), 7.51 (d, J=6.8 Hz,2H), 7.47-7.41 (m, 2H), 7.40-7.34 (m, 1H), 6.98-6.93 (m, 2H), 6.78 (d,J=0.9 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 5.23 (s, 2H), 3.79 (s, 3H), 2.25(q, J=7.6 Hz, 2H), 1.11-1.05 (m, 3H); LC-MS: RT=0.79 min, MS (ESI) m/z:408.1 (M+H)⁺

Example 1 Example 1B

(50 mg, 0.123 mmol) in POCl₃ (0.5 mL) was heated at 105° C. under Argonfor 45 min. After the reaction mixture was cooled to rt, it was dilutedwith EtOAc, quenched with cold water. The organic layer was washed with1.5 M dipotassium phosphate, brine, dried over sodium sulfate andconcentrated. The crude residue was purified using a preparative HPLC(method A, 70-100% B in 10 mins; RT=6.0 min). The desired fractions wereplaced in a speedvac overnight to remove solvent, then lyophilized togive Example 1 (5.0 mg, 0.012 mmol, 9.63% yield) as a slightly brownlyophilate. ¹H NMR (400 MHz, chloroform-d) δ 7.54-7.45 (m, 3H), 7.40 (t,J=7.4 Hz, 2H), 7.34 (d, J=7.0 Hz, 1H), 7.11 (s, 1H), 6.68 (s, 1H), 6.40(d, J=1.3 Hz, 1H), 5.18 (s, 2H), 3.83 (s, 3H), 2.92 (q, J=7.6 Hz, 2H),1.43 (t, J=7.5 Hz, 3H). LC-MS: RT=1.15 min, MS (ESI) m/z: 390.4 (M+H)⁺Analytical HPLC purity (method A): 93%.

Example 24-(4-(((2-(2-ethylimidazo[2,1-b][1,3,4]oxadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

Example 2A2-(2-ethylimidazo[2,1-b][1,3,4]oxadiazol-6-yl)-6-methoxybenzofuran-4-ol

Example 1

40 mg, 0.103 mmol) and pentamethylbenzene (107 mg, 0.719 mmol weredissolved in dichloromethane (2.0 mL) and cooled to −78° C. 1.0 M borontrichloride in heptane (0.267 mL, 0.267 mmol) was added. The reactionmixture was stirred at −78° C. for 40 min, and at rt for 40 min. Thereaction mixture was diluted with EtOAc, quenched with 0.5 N HCl andextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried over sodium sulfate and concentrated. The crude product waspurified by flash chromatography (loading in chloroform/MeOH, 10% to100% EtOAc in hexanes over 10 min using a 4 g silica gel cartridge). Thedesired fractions were combined and concentrated to yield Example 2A (23mg, 0.077 mmol, 74.8% yield) as a pale yellow solid. ¹H NMR (400 MHz,methanol-d₄) δ 7.57 (s, 1H), 7.03 (s, 1H), 6.61 (dd, J=2.0, 0.9 Hz, 1H),6.32 (d, J=2.0 Hz, 1H), 3.84-3.82 (s, 3H), 2.96 (q, J=7.6 Hz, 2H), 1.27(t, J=7.2 Hz, 3H); LC-MS: RT=0.76 min, MS (ESI) m/z: 300.0 (M+H)⁺.

Example 2B 4-(4-(Bromomethyl)thiazol-2-yl)-N,N-dimethylbenzamide

To an ice-cold mixture of4-(4-(hydroxymethyl)thiazol-2-yl)-N,N-dimethylbenzamide (0.525 g, 2.000mmol, for preparation, see PCT Int. Appl. (2013), WO 2013163279) in DCM(15 mL) under N₂ was added phosphorous tribromide (0.095 mL, 1.000 mmol)dropwise. After 5 min the cooling bath was removed and the mixture wasstirred at room temperature for 3 h, at which time LCMS showed that nostarting material remained. The resulting white suspension was pouredinto a mixture of ice (50 mL) and saturated aqueous NaHCO₃ (50 mL) andextracted with DCM (2×100 mL). The combined organic phase was washed(brine), dried (Na₂SO₄) and evaporated to give a pale yellow gum. Flashchromatography (Isco/50-100% EtOAc-DCM; rapid elution on a 24 g column)afforded Example 2B (0.549 g, 84% yield) as a colorless gum whichsolidified on standing in vacuo to give a white solid. This material wasused as such in the next step. ¹HNMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=8.6Hz, 2H), 7.87 (s, 1H), 7.53 (d, J=8.2 Hz, 2H), 4.81 (s, 2H), 2.99 (br s,3H), 2.92 (br s, 3H). HRMS (ESI): Calcd. for C₁₃H₁₄BrN₂OS [M+H]+m/z325.0010. found 325.0003.

Example 2

To Example 2A (23 mg, 0.077 mmol) in DMF (2.0 mL) at rt was added cesiumcarbonate (43.8 mg, 0.134 mmol). The mixture was stirred at rt for 10min, followed by addition of Example 2B (27.5 mg, 0.085 mmol). Thereaction mixture was stirred at rt for 30 min. It was diluted withEtOAc, washed with water, brine, dried over sodium sulfate andconcentrated. The crude was dissolved in DMSO and purified viapreparative LC/MS (method B, 20-75% B over 20 min, then a 5-min hold at100% B). Fractions containing the desired product were combined anddried via centrifugal evaporation to yield Example 2 (26.6 mg, 0.046mmol, 59.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.06-7.90 (m, 4H), 7.53(d, J=7.9 Hz, 2H), 7.02 (s, 1H), 6.84 (s, 1H), 6.64 (s, 1H), 5.38 (s,2H), 3.82 (s, 3H), 3.40-3.35 (m, 1H), 3.04-2.86 (m, 7H), 1.30 (t, J=7.3Hz, 3H); LC-MS: RT=2.05 min, MS (ESI) m/z: 544.2 (M+H)⁺. Analytical HPLCpurity (method B): 94%.

Example 36-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-methylimidazo[2,1-b][1,3,4]oxadiazole

Example 3A1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-(2-imino-5-methyl-1,3,4-oxadiazol-3(2H)-yl)ethanonehydrobromide

A suspension of 5-methyl-1,3,4-oxadiazol-2-amine (206 mg, 2.083 mmol)and 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (521 mg,1.389 mmol, for preparation, see PCT Int. Appl. (2013), WO 2013163241)in isopropanol (12 mL) was heated in a sealed vial at 78° C. Thesuspension turned to a clear solution. The reaction mixture was keptstirring at 78° C. overnight. Precipitate formed at the end of thereaction. The reaction mixture was triturated with diethyl ether. Theprecipitate was collected by filtration, washed with diethyl ether anddried under vacuum to give Example 3A (570 mg, 1.202 mmol, 87% yield).¹H NMR (500 MHz, DMSO-d₆) δ 8.23 (s, 1H), 7.54 (d, J=7.2 Hz, 2H), 7.44(t, J=7.4 Hz, 2H), 7.39 (d, J=7.4 Hz, 1H), 6.98 (s, 1H), 6.67 (d, J=1.7Hz, 1H), 5.65 (s, 2H), 5.30 (s, 2H), 3.86 (s, 3H), 2.51 (s, 3H). LC-MS:RT=0.90 min, MS (ESI) m/z: 394.05 (M+H)⁺

Example 3BN-(4-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)acetamide

To a suspension of Example 3A (630 mg, 1.328 mmol) in water (12 mL) andTHF (10 mL) was added 1.0 N NaOH (1.727 mL, 1.727 mmol). The reactionmixture turned clear and was heated at 60° C. for 2.5 h. LCMS indicateda clean reaction. The reaction mixture was diluted with EtOAc and the pHwas adjusted to 4-5 with 0.5 N HCl. The organic layer was washed withbrine, dried over sodium sulfate and concentrated to give Example 3B(447 mg, 1.136 mmol, 86% yield) as a brown solid. It was used for thenext step without further purification. ¹H NMR (400 MHz, chloroform-d) δ7.41-7.23 (m, 5H), 6.70 (br. s., 1H), 6.47 (br. s., 1H), 6.36 (br. s.,1H), 6.23 (br. s., 1H), 5.02 (br. s., 2H), 3.66 (s, 3H), 2.04 (s, 3H).LC-MS: RT=0.953 min, MS (ESI) m/z: 394.05 (M+H)+⁺.

Example 3

Example 3B (50 mg, 0.127 mmol) in POCl₃ (0.5 mL) was heated at 105° C.under Argon for 45 min. After the reaction mixture was cooled to rt, itwas diluted with EtOAc, quenched with cold water. The organic layer waswashed with 1.5 M dipotassium phosphate, brine, dried over sodiumsulfate and concentrated. The crude product was purified by flashchromatography (loading in chloroform, 0% to 45% EtOAc in hexanes over10 min using a 4 g silica gel cartridge). The desired fractions werecombined and concentrated to yield a crude product (12 mg). The crudeproduct was dissolved in DMSO and purified via preparative LC/MS (methodB, 25-100% B over 20 min, then a 5-min hold at 100% B). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to yield Example 3 (7.8 mg, 0.021 mmol, 16% yield) as awhite solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.00 (s, 1H), 7.50 (d, J=7.0Hz, 2H), 7.41 (t, J=7.2 Hz, 2H), 7.34 (d, J=6.7 Hz, 1H), 6.95 (s, 1H),6.81 (br. s., 1H), 6.51 (br. s., 1H), 5.24 (s, 2H), 3.77 (s, 3H), 2.58(s, 3H). LC-MS: RT=2.1 min, MS (ESI) m/z: 376.1 (M+H)⁺. Analytical HPLCpurity (method B): 100%.

Example 44-(4-(((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]oxadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide

Example 4A6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]oxadiazol-6-yl)benzofuran-4-ol

Example 3

(30 mg, 0.080 mmol) and pentamethylbenzene (83 mg, 0.559 mmol) weredissolved in dichlooromethane (2.0 mL) and cooled to −78° C. 1.0 M borontrichloride in heptane (0.208 mL, 0.208 mmol) was added. The reactionmixture was stirred at −78° C. for 40 min, and at rt for 40 min. Thereaction mixture was diluted with EtOAc, quenched with 0.5 N HCl andextracted thrice with EtOAc. The combined organic layers were washedwith brine, dried over sodium sulfate and concentrated. The crudeproduct was purified by flash chromatography (loading inchloroform/MeOH, 5% to 100% EtOAc in dichloromethane over 10 min using a4 g silica gel cartridge). The desired fractions were combined andconcentrated to yield Example 4A (10 mg, 0.035 mmol, 43.9% yield) as apale yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ 7.48 (s, 1H), 6.93(s, 1H), 6.51 (d, J=1.1 Hz, 1H), 6.22 (d, J=2.0 Hz, 1H), 3.73 (s, 3H),2.54 (s, 3H). LC-MS: RT=0.70 min, MS (ESI) m/z: 286.0 (M+H)⁺,

Example 4 Example 4A

(20 mg, 0.070 mmol) and4-(4-(hydroxymethyl)thiazol-2-yl)-N,N-dimethylbenzamide (20.23 mg, 0.077mmol, for preparation, see PCT Int. Appl. (2013), WO 2013163279) wereplaced in a flask and vacuumed for 15 min. The flask was backfilled withnitrogen and dry THF (995 μl) was added. tri-n-Butylphosphine (43.2 μl,0.175 mmol) was added in one portion. A solution of1,1′-(azodicarbonyl)dipiperidine (44.2 mg, 0.175 mmol) in dry THF (497μl) was added. The reaction mixture was stirred at rt overnight, dilutedwith EtOAc, washed with 0.5 N HCl, brine and dried over sodium sulfate.After evaporation of solvent, the crude residue was purified using apreparative HPLC (method A, 45-100% B in 10 min. RT=4.2 min). Thedesired fractions were placed in a speedvac over night to removesolvent, then lyophilized to give Example 4 (11.4 mg, 0.020 mmol, 29.2%yield) as a white lyophilate. ¹H NMR (400 MHz, chloroform-d) δ 8.04-7.99(m, 2H), 7.55-7.49 (m, 3H), 7.42 (s, 1H), 7.14 (s, 1H), 6.72-6.69 (m,1H), 6.46 (d, J=2.0 Hz, 1H), 5.39 (d, J=0.7 Hz, 2H), 3.85 (s, 3H), 3.14(s, 3H), 3.02 (s, 3H), 2.62 (s, 3H); LC-MS: RT=0.858 min, MS (ESI) m/z:530.1 (M+H)⁺, Analytical HPLC purity (method B): 95%.

In a similar manner, the following compounds could be prepared:

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Biology

The term “PAR4 antagonist” denotes an inhibitor of platelet aggregationwhich binds PAR4 and inhibits PAR4 cleavage and/or signaling. Typically,PAR4 activity is reduced in a dose dependent manner by at least 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to suchactivity in a control cell. The control cell is a cell that has not beentreated with the compound. PAR4 activity is determined by any standardmethod in the art, including those described herein (for example calciummobilization in PAR4 expressing cells, platelet aggregation, plateletactivation assays measuring e.g., calcium mobilization, p-selectin orCD40L release, or thrombosis and hemostasis models). The term “PAR4antagonist” also includes a compound that inhibits both PAR1 and PAR4.

It is desirable to find compounds with advantageous and improvedcharacteristics compared with known anti-platelet agents, in one or moreof the following categories that are given as examples, and are notintended to be limiting: (a) pharmacokinetic properties, including oralbioavailability, half life, and clearance; (b) pharmaceuticalproperties; (c) dosage requirements; (d) factors that decrease bloodconcentration peak-to-trough characteristics; (e) factors that increasethe concentration of active drug at the receptor; (f) factors thatdecrease the liability for clinical drug-drug interactions; (g) factorsthat decrease the potential for adverse side-effects, includingselectivity versus other biological targets; (h) improved therapeuticindex with less propensity for bleeding; and (h) factors that improvemanufacturing costs or feasibility.

The term “compound”, as used herein, means a chemical, be itnaturally-occurring or artificially-derived. Compounds may include, forexample, peptides, polypeptides, synthetic organic molecules, naturallyoccurring organic molecules, nucleic acid molecules, peptide nucleicacid molecules, and components and derivatives thereof.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or nonhumanorganism that could potentially benefit from treatment with a PAR4antagonist. Exemplary subjects include human beings of any age with riskfactors for cardiovascular disease, or patients that have alreadyexperienced one episode of cardiovascular disease. Common risk factorsinclude, but are not limited to, age, male sex, hypertension, smoking orsmoking history, elevation of triglycerides, elevation of totalcholesterol or LDL cholesterol.

In some embodiments, the subject is a species having a dual PAR1/PAR4platelet receptor repertoire. As used herein, the term “dual PAR1/PAR4platelet receptor repertoire” means that a subject expresses PAR1 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR1/PAR4 platelet receptor repertoire include human beings, non-humanprimates, and guinea pigs.

In other embodiments, the subject is a species having a dual PAR3/PAR4platelet receptor repertoire. As used herein, the term “dual PAR3/PAR4platelet receptor repertoire” means that a subject expresses PAR3 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR3/PAR4 platelet receptor repertoire include rodents and rabbits.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting its development; and/or(b) relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit and/or antagonize PAR4 and/or toprevent or treat the disorders listed herein. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi) within a blood vessel that may causeischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid interna, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population. (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl.J. Med., 334(11):677-681 (1996); Blom, J. W. et al., JAMA,293(6):715-722 (2005).) Hence, the most common cancers associated withthrombosis in men are prostate, colorectal, brain, and lung cancer, andin women are breast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular weight heparin preparations have been approvedby the FDA for these indications.

The term “pharmaceutical composition”, as used herein, means anycomposition, which contains at least one therapeutically or biologicallyactive agent and is suitable for administration to the patient. Any ofthese formulations can be prepared by well-known and accepted methods ofthe art. See, for example, Gennaro, A. R., ed., Remington: The Scienceand Practice of Pharmacy, 20th Edition, Mack Publishing Co., Easton, Pa.(2000).

The invention includes administering to a subject a pharmaceuticalcomposition that includes a compound that binds to PAR4 and inhibitsPAR4 cleavage and/or signaling (referred to herein as a “PAR4antagonist” or “therapeutic compound”).

The compounds of this disclosure can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The preferred dose of the PAR4 antagonist is a biologically active dose.A biologically active dose is a dose that will inhibit cleavage and/orsignaling of PAR4 and have an anti-thrombotic effect. Desirably, thePAR4 antagonist has the ability to reduce the activity of PAR4 by atleast 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or morethan 100% below untreated control levels. The levels of PAR4 inplatelets is measured by any method known in the art, including, forexample, receptor binding assay, platelet aggregation, plateletactivation assays (e.g., p-selectin expression by FACS), Western blot orELISA analysis using PAR4 cleavage sensitive antibodies. Alternatively,the biological activity of PAR4 is measured by assessing cellularsignaling elicited by PAR4 (e.g., calcium mobilization or other secondmessenger assays).

In some embodiments, a therapeutically effective amount of a PAR4compound is preferably from about less than 100 mg/kg, 50 mg/kg, 10mg/kg, 5 mg/kg, 1 mg/kg, or less than 1 mg/kg. In a more preferredembodiment, the therapeutically effective amount of the PAR4 compound isless than 5 mg/kg. In a most preferred embodiment, the therapeuticallyeffective amount of the PAR4 compound is less than 1 mg/kg. Effectivedoses vary, as recognized by those skilled in the art, depending onroute of administration and excipient usage.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration may contain a water soluble saltof the active ingredient, suitable stabilizing agents, and if necessary,buffer substances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Dispersion

A spray dried dispersion can be prepared for oral administration bymethods know to one skilled in the art.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, or Ia, preferably, acompound selected from one of the examples, generally the amount of eachcomponent in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the examples and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Additionally, certain compounds disclosed herein may be useful asmetabolites of other compounds. Therefore, in one embodiment, compoundsmay be useful either as a substantially pure compound, which may alsothen be incorporated into a pharmaceutical composition, or may be usefulas metabolite which is generated after administration of the prodrug ofthat compound. In one embodiment, a compound may be useful as ametabolite by being useful for treating disorders as described herein.

The activity of the PAR4 antagonists of the present invention can bemeasured in a variety of in vitro assays. Exemplary assays are shown inthe Examples below.

The FLIPR assay is an exemplary in vitro assay for measuring theactivity of the PAR4 antagonists of the present invention. In thisassay, intracellular calcium mobilization is induced in PAR4 expressingcells by a PAR4 agonist and calcium mobilization is monitored. See,e.g., Example A.

AYPGKF is a known PAR4 agonist. An alternative PAR4 agonist isH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂.H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ has improved agonistactivity as compared to AYPGKF with an EC₅₀ that is 10 fold lower thanthe EC₅₀ for AYPGKF in the FLIPR assay.H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ can be synthesizedusing methods well known to those of skill in the art.

The FLIPR assay can also be used as a counterscreen to test agonistactivity or PAR1 antagonist activity in a cell line that expresses bothPAR1 and PAR4. The PAR1 antagonist activity can be tested by the abilityof the compound to inhibit calcium mobilization induced by the PAR1agonist peptide SFLLRN or other PAR1 agonist peptides.

The compounds of the current invention can be tested in vitro for theirability to inhibit platelet aggregation induced by gamma-thrombin asshown in Example B. Gamma-thrombin, a proteolytic product ofalpha-thrombin which no longer interacts with PAR1, selectively cleavesand activates PAR4 (Soslau, G. et al., “Unique pathway ofthrombin-induced platelet aggregation mediated by glycoprotein Ib”, J.Biol. Chem., 276:21173-21183 (2001)). Platelet aggregation can bemonitored in a 96-well microplate aggregation assay format or usingstandard platelet aggregometer. The aggregation assay can also beemployed to test the selectivity of the compound for inhibiting plateletaggregation induced by PAR4 agonist peptides, PAR1 agonist peptide, ADP,or thromboxane analogue U46619.

Example C is an alpha-thrombin-induced platelet aggregation assay.Alpha-thrombin activates both PAR1 and PAR4. The ability of a compoundsof the present invention to inhibit platelet aggregation may be measuredusing a standard optical aggregometer. Example D is a tissuefactor-induced platelet aggregation assay. The conditions in this assaymimic the physiological events during thrombus formation. In this assay,platelet aggregation in human PRP was initiated by the addition oftissue factor and CaCl₂. Tissue factor, the initiator of the extrinsiccoagulation cascade, is highly elevated in human atherosclerotic plaque.Exposure of blood to tissue factor at the atherosclerotic site triggersa robust generation of thrombin and induces the formation of obstructivethrombi.

The efficacy of the PAR4 antagonists of the present invention inpreventing thrombosis can also be measured in a variety of in vivoassays. Exemplary mammals that can provide models of thrombosis andhemostasis to test the effectiveness of the PAR4 antagonists of thepresent invention as antithrombotic agents include, but are not limitedto, guinea pigs and primates. Relevant efficacy models include, but arenot limited to, electrolytic injury-induced carotid artery thrombosis,FeCl₃-induced carotid artery thrombosis and arteriovenous-shuntthrombosis. Models of kidney bleeding time, renal bleeding time andother bleeding time measurements can be used to assess the bleeding riskof the antithrombotic agents described in the current invention. ExampleF describes an in vivo model of arterial thrombosis in cynomolgusmonkeys. Compounds of the present invention can be tested in this modelfor their ability to inhibit thrombus formation induced by electrolyticinjury of the carotid artery. Demonstration of efficacy in this modelsupports the utility of PAR4 antagonists of the present invention fortreatment of thromboembolic diseases.

Assays

Materials

1) PAR1 and PAR4 Agonist Peptides

SFFLRR is a known high affinity PAR1 selective agonist peptide.(Reference: Seiler, S. M., “Thrombin receptor antagonists”, Seminars inThrombosis and Hemostasis, 22(3):223-232 (1996).) The PAR4 agonistpeptides AYPGKF and H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂were synthesized. H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂showed improved PAR4 agonist activity over AYPGKF in the FLIPR assay(EC₅₀ value of 8 M forH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 60 M for AYPGKF)and in washed platelet aggregation assay (EC₅₀ value of 0.9 M forH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 12 μM forAYPGKF).

2) PAR4 Expressing Cells

HEK293 cells stably expressing PAR4 were generated by a standard methodof transfection of human PAR4 (F2R²³) cDNA expression vector andselected based on PAR4 protein expression or mRNA expression. Thosecells demonstrated functional responses to PAR4 agonist peptide-inducedintracellular calcium elevation using FLIPR® (Fluorometric Imaging PlateReader; Molecular Devices Corp.). These cells also express endogenousPAR1 and can elicit calcium signal upon stimulation with PAR1 agonistpeptide. Therefore, the same cells were also used to determineselectivity against PAR1 and agonist activity for both receptors. Cellsfrom HEK293 PAR4 Clone 1.2A (BMS Arctic ID 383940) were propagated andused for calcium mobilization studies.

3) Preparation of Platelet Rich Plasma (PRP)

Human blood was collected in 3.8% sodium citrate at a ratio of 1 ml per9 ml blood and centrifuged in a Sorvall® RT6000B centrifuge at 900revolution per minute (rpm) at room temperature (RT) for 15 minutes. PRPwas collected and used for aggregation assay. Refludan (Berlex Labs,Wayne, N.J.), a recombinant hirudin, at a final concentration of 1unit/mL was added to the sample to selectively prevent PAR1 activationinduced by residual alpha-thrombin contamination. The remaining bloodsample was centrifuged at 2500 rpm at room temperature for 5 minutes tocollect platelet-poor plasma (PPP).

4) Preparation of Washed Platelets (WP)

Human blood was collected in ACD (85 mM tri-sodium citrate, 78 mM citricacid, 110 mM D-glucose, pH 4.4) at a ratio of 1.4 ml per 10 ml blood.PRP was isolated by centrifugation at 170 g for 14 minutes and plateletswere further pelleted by centrifugation at 1300 g for 6 minutes.Platelets were washed once with 10 ml ACD containing 1 mg/ml bovineserum albumin. Platelets were resuspended at ˜2.5×10⁸/ml in Tyrode'sBuffer (137 mM NaCl, 2 mM KCl, 1.0 mM MgCl₂, 1 mM CaCl₂, 5 mM glucose,20 mM HEPES pH 7.4).

Example A FLIPR Assay in PAR4-Expressing HEK293 Cells

FLIPR-based calcium mobilization assay in HEK293 cells was used tomeasure PAR4 antagonism, agonism, and selectivity against PAR1. Theactivity of the PAR4 antagonists of the present invention were tested inPAR4 expressing cells by monitoringH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂-induced intracellularcalcium mobilization. Counter screens for agonist activity and PAR1antagonist activity were also performed. Briefly, PAR1/PAR4-expressingHEK293 cells were grown in DMEM (Life Technology, Grand Island, N.Y.)containing 10% heat-inactivated FBS, 1% Penicillin-Streptomycin, 10μg/mL blasticidin, and 100 μg/mL Zeocin at 37° C. with 5% CO₂. Cellswere plated overnight prior to the experiment in a black 384-wellPurecoat Amine clear bottom plate (Becton Dickinson Biosciences, SanJose, Calif.) at 10,000 cells/well in 30 μL growth medium and incubatedin a humidified chamber at 37° C. with 5% CO₂ overnight. Prior tocompound addition, the cell medium was replaced with 40 μL of IX calciumand magnesium-containing Hank's Balanced Saline Solution (HBSS) (with 20mM HEPES) and 1:1000 diluted fluorescent calcium indicator (CodexBiosolutions, Gaithersburg, Md.). After a 30 minute incubation period at37° C. and a further 30 minute incubation and equilibration period atroom temperature, 20 μL test compound (diluted in 1×HBSS buffer) wasadded at various concentrations at 0.17% dimethyl sulfoxide (DMSO) finalconcentration. Changes in fluorescence intensity were measured using aFunctional Drug Screening System (FDSS, Hamamatsu, Japan) to determineagonist activities. The cells were then incubated for 30 minutes at roomtemperature followed by addition of 20 μL of agonist peptide forantagonist activity measurement. The PAR4 agonist peptide(H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂) and the PAR1agonist peptide (SFFLRR) were routinely tested to ensure a properresponse at the EC₅₀ value in the assay (˜5 μM for PAR4 agonist peptideand ˜2 μM for PAR1 agonist peptide). Compound potency was derived from11-point concentration-response curves.

Example B Gamma Thrombin Induced Platelet Aggregation Assays

The ability of the compound(s) of the current invention to inhibitplatelet aggregation induced by gamma-thrombin was tested in a 96-wellmicroplate aggregation assay format. Briefly, 90 μL of PRP or washedplatelets were pre-incubated for 5 minutes at 37° C. with 3-foldserially diluted test compound, which was prepared as a 100-fold stocksolution in dimethyl sulfoxide (DMSO). Aggregation was initiated byaddition of 10 μL of gamma-thrombin (Haematologic Technologies, Inc.Essex Junction, Vt.) at 50-100 nM final concentration, which wastitrated daily to achieve 80% platelet aggregation. The plate was thenplaced into a SpectraMax® Plus Plate Reader (Molecular Devices) at 37°C. Platelet aggregation was monitored at a wavelength of 405 nm using akinetic analysis mode. Prior to the first data collection time point,the plate was shaken for 10 seconds to allow thorough mixing. Data wassubsequently collected every 10 seconds for up to 7 minutes total. Datawas collected using SoftMax® 5.4.1 software and exported to MicrosoftExcel for analysis. The optical density (OD) values at the time pointthat achieved 75% platelet activation by agonist alone were used foranalysis. The OD value from a PRP sample without any treatment served asODmaximum, and the OD value from a PPP sample containing no plateletsserved as the ODminimum. Inhibition of platelet aggregation (IPA) wascalculated based on the formula: %IPA=(100−100*[ODcompound−ODminimum]/[ODmaximum−ODminimum]). The IC₅₀value of the test compound was calculated by fitting the % IPA values tothe one-site concentration response equation: Y=A+(B−A)/{1+(C/X)^D]},using XLfit for 32 bit Excel® Version 2 Build 30 (ID Business SolutionsLimited).

The aggregation assays were also employed to test the selectivity of thecompound against other platelet receptors by using SFFLRR for PAR1,collagen (Chrono-Log, Havertown, Pa.) for collagen receptors, ADP forP2Y1 and P2Y12 and U46619 (Cayman Chemical, Ann Arbor, Mich.) forthromboxane receptors.

Example C Alpha-Thrombin Induced Platelet Aggregation Assays

The ability of PAR4 antagonists to inhibit platelet aggregation inducedby alpha-thrombin can be tested using human washed platelets. Theantagonists are pre-incubated with washed platelets for 20 min.Aggregation is initiated by addition of 1.5 nM alpha-thrombin(Haematologic Technologies, Essex Junction, Vt.) to 300 μl of washedplatelets at stirring speed of 1000 rpm. Platelet aggregation ismonitored using an Optical Aggregometer (Chrono-Log, Havertown, Pa.) andthe area under the curve (AUC) at 6 min was measured. IC₅₀ values arecalculated using vehicle control as 0% inhibition.

Example D Tissue Factor-Induced Platelet Aggregation Assay

The ability of PAR1 or PAR4 antagonists to inhibit platelet aggregationinduced by endogenous thrombin can be tested in a tissue factor drivenaggregation assay. Aggregation is initiated by addition of CaCl₂ andrecombinant human tissue factor, which results in the generation ofthrombin through activation of the coagulation pathway in the plasma.Anticoagulant agents such as corn trypsin inhibitor (HaematologicTechnologies, Essex Junction, Vt.) at 50 μg/ml and PEFABLOC® FG(Centerchem, Norwalk, Conn.) are also added to the sample to preventfibrin clot formation during the time of the study. Platelet aggregationis monitored using standard instrumentation including opticalaggregometer or impedance aggregometer.

Example E

As indicated above, the FLIPR assay, an in vitro assay, measures thePAR4 antagonist activity of compounds tested as described in Example A.Examples 1-4 have been tested in the PAR4 FLIPR assay and have beenfound to have an EC₅₀<5 μM.

Example F Cynomolgus Monkey Electrolytic Injury-induced Carotid ArteryThrombosis Model

Healthy cynomolgus monkeys can be used in the study. These monkeys areretired from other pharmacokinetic and pharmacodynamic studies and hadat least a 4-week washout period.

On the day of the study, compounds or vehicles are administered orallyat 1 to 2 hours before the experiment. Monkeys are then sedated byintramuscular administration of 0.2 mg/kg atropine, 5 mg/kg TELAZOL®(tiletamine/zolazepam) and 0.1 mg/kg hydromorphone to facilitateplacement of an endotracheal tube. An intravenous catheter is placed inthe left cephalic vein for fluid administration to prevent dehydration.Animals are then administered with an inhalant anesthetic, isoflurane(1-5% to effect) and oxygen, ventilated, and placed on athermostatically controlled heating pad to maintain the body temperatureat 37° C. General anesthesia is maintained at a surgical plane usinginhaled isoflurane and oxygen. The left brachial artery is cannulated torecord blood pressure and heart rate. Blood pressure and heart rate aremonitored to maintain normal vital signs.

The carotid arterial thrombosis model in monkeys is based on a rabbitarterial thrombosis model, as described by Wong et al. (Wong, P. C. etal., “Nonpeptide factor Xa inhibitors: II. Antithrombotic evaluation ina rabbit model of electrically induced carotid artery thrombosis”, J.Pharmacol. Exp. Ther., 295:212-218 (2002).) Thrombosis is induced byelectrical stimulation of the carotid artery for 5 min at 10 mA using anexternal stainless-steel bipolar electrode. Carotid blood flow ismeasured with an appropriately sized TRANSONIC® flow probe and aTRANSONIC® perivascular flowmeter (TS420 Model, Transonic Systems Inc.,Ithaca, N.Y.). It is continuously recorded over a 90-min period tomonitor thrombosis-induced occlusion. Integrated carotid blood flow ismeasured by the area under the flow-time curve. It is expressed aspercent of total control carotid blood flow, which would result ifcontrol blood flow had been maintained continuously for 90 min. Inaddition, thrombus from the injured artery is removed, blotted twice ona weighing paper to remove residual fluid, and weighed.

While it is apparent that the embodiments of the application hereindisclosed are well suited to fulfill the objectives stated above, itwill be appreciated that numerous modifications and other embodimentsmay be implemented by those skilled in the art, and it is intended thatthe appended claims cover all such modifications and embodiments thatfall within the true spirit and scope of the present application.

What is claimed is:
 1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein: the dashed line represents an optionaldouble-bond X¹ is O and X² is CH, CR¹⁰, or N; or X¹ is N and X² is O; orX¹ is N, CH, or CR¹⁰, and X² is S; or X¹ is N and X² is NH; or X¹ is NHand X² is CH or CR¹⁰; or X¹ is CH or CR¹⁰ and X² is NH; X³, X⁴ and X⁵are independently selected from CR³ or N; W is O or S; R¹ isindependently selected from the group consisting of: halo, C₁-C₄ alkyl,C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy, C₁-C₂alkoxy-C₁-C₂ alkyl, tetrahydrofuran-2-yl; C₁-C₄ alkylthio, C₁-C₄alkylNH—, (C₁-C₄ alkyl)₂N—, halo-C₁-C₂-alkyl, where halo is F or Cl,halo-C₃-C₄ cycloalkyl, halo-C₁-C₂ alkoxy, and halo-C₁-C₂ alkylthio; R²is selected from the group consisting of: H, halo, C₁-C₄ alkyl, C₁-C₄alkoxy, and halo-C₁-C₂-alkyl, where halo is F or Cl, and cyano; R³ isselected from the group consisting of H, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo, OH, CN, OCF₃, OCHF₂,OCH₂F, C₁-C₂-alkoxy-C₁-C₂-alkoxy, halo-C₁-C₃-alkyl, benzyloxysubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃,5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,and —(CH₂)_(n)-phenyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,di-C₁-C₄-alkylamino, and cyano; R⁴ and R⁵ are independently selectedfrom H, C₁-C₆ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ fluoroalkyl or R⁴ and R⁵can be taken together with the carbon to which they are attached to forma C₃-C₇ cycloalkyl ring;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one O, N or S atom, or a 6-memberedheteroaryl ring, containing at least one nitrogen atom; R⁶ is selectedfrom the group consisting of H, halo, OCF₃, OCHF₂, OH, CN, NO₂, NR¹¹R¹²,COOH, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl,S(═O)₂NR¹¹R¹², and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or R⁶ is B-D-, where D is alinker, which is selected from a single bond, —O—, —S—,

C₁-C₄ alkylene substituted by 0 to 4 groups independently selected fromhalo or OH, C₁-C₄ alkyleneoxy, C₁-C₄ alkylenethio, C₁-C₄alkyleneoxy-C₁-C₄-alkylene, C₁-C₄-alkylenethio-C₁-C₄-alkylene,—S—C₁-C₄-alkylene, —O—C₁-C₄-alkylene, —NHC(═O)— and —C(═O)NH—, and C₂-C₆alkenylene, B is selected from the group consisting of a C₆-C₁₀ aryl, a5- to 10-membered heteroaryl, a 4- to 10-membered heterocyclylcontaining carbon atoms and 1 to 4 additional heteroatoms selected fromN, O, and S, a C₃-C₈ cycloalkyl which may contain unsaturation and aC₅-C₁₁ spirocycloalkyl which may contain unsaturation and optionallycontaining 1 to 3 heteroatoms selected from O, N or S, all of which maybe optionally substituted with one or more R^(b), R^(c), R^(d) andR^(e); R^(b), R^(c), R^(d) and R^(e), at each occurrence, areindependently selected from the group consisting of halo, halo-C₁-C₄alkoxy, OH, CN, NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio,C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,N(R¹³)(C═O)OR¹⁴, SO₂R¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴,O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₃-C₆ cycloalkyl, a 4-to 10-membered heterocyclyloxy; a C₁-C₅ alkyl substituted by 0 to 7groups independently selected from halo, CF₃, OCF₃, OH, CN,hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to10-membered heterocyclyloxy, C₁-C₄-alkylcarbonyloxy and C₁-C₄ alkylthio;—(CHR¹³)_(n)-5- or 6-membered heteroaryl substituted by 0 to 3 groupsindependently selected from the group consisting of halo, C₁-C₄ alkoxy,C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and CF₂CH₃; —(CHR¹³)_(n)-4- to10-membered-heterocyclyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, and CF₂CH₃; di-C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆ cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀arylcarbonyl, C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, and a C₆-C₁₀ arylsubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃; R¹⁰ isselected from the group consisting of C₁-C₄ alkyl, halo, cyano, C₁-C₄alkoxy, and halo-C₁-C₂-alkyl, where halo is F or Cl, R¹¹ and R¹² areindependently, at each occurrence, selected from the group consistingof: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,—(CR¹⁴R¹⁴)_(n)-phenyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,di-C₁-C₄-alkylamino, and cyano, —(CHR¹³)_(n)—C₃-C₆-cycloalkylsubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n)-4- to10-membered-heterocyclyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, CF₃, OCF₃, 5- or 6-memberedheteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,—(CHR¹³)_(n)-5- to 10-membered-heteroaryl substituted by 0 to 3 groupsindependently selected from the group consisting of halo, CF₃, OCF₃, 5-or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,di-C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,di-C₁-C₄-alkoxy-C₁-C₄-alkyl, di-C₁-C₄-alkylaminophenyl,hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-alkylcarbonyl, phenylcarbonyl;C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl, amino-C₁-C₄-alkylcarbonyl, 4-to 10-membered-heterocyclyl-carbonyl, and alternatively, R¹¹ and R¹²,when attached to the same nitrogen, combine to form a 4- to 10-memberedmono- or bicyclic heterocyclic ring containing carbon atoms substitutedby 0 to 3 groups independently selected from the group consisting ofhalo, cyano, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2additional heteroatoms selected from N, NR¹³, O and S(O)_(p); R¹³ isindependently, at each occurrence, selected from the group consisting ofH, C₁-C₆ alkyl and —(CH₂)phenyl; R¹⁴ is independently, at eachoccurrence, selected from the group consisting of H, C₁-C₆ alkyl,halo-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino),(a 5- to 10-membered heteroarylcarbonylamino) and —(CH₂)_(n)phenylsubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃,5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,R⁷ is selected from the group consisting of H, halo, hydroxyl, cyano,oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,halo-C₁-C₄-alkyl, C₁-C₄-alkoxy, and halo-C₁-C₄-alkoxy or R⁶ and R⁷ canbe taken together with the carbons to which they attach to form a C₆-C₁₀aryl ring; n, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5;and p, at each occurrence, is selected from 0, 1 and
 2. 2. The compoundof claim 1, or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate or prodrug thereof, wherein: X¹ is O and X² is CH, CR¹⁰,or N; or X¹ is N and X² is O; or X¹ is N and X² is S; X³, X⁴ and X⁵ areindependently selected from CR³ or N; W is O; R¹ is independentlyselected from the group consisting of: halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ alkylthio, halo-C₁-C₂-alkyl, where halo is F or Cl, R² is H; R³ isselected from the group consisting of C₁-C₄ alkoxy, C₁-C₄ alkylthio,halo, OCF₃, OCHF₂, OCH₂F, or halo-C₁-C₃-alkyl; R⁴ and R⁵ areindependently selected from H, C₁-C₆ alkyl, C₁-C₄ fluoroalkyl or R⁴ andR⁵ can be taken together with the carbon to which they are attached toform a C₃-C₇ cycloalkyl ring;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one O, N or S atom, or a 6-memberedheteroaryl ring, containing at least one nitrogen atom; R⁶ is selectedfrom the group consisting of H, halo, OCF₃, OCHF₂, OH, CN, NO₂, NR¹¹R¹²,COOH, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl,S(═O)₂NR¹¹R¹², and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or R⁶ is B-D-, where D is alinker, which is selected from a single bond, —O—, —S—,

C₁-C₄ alkylene substituted by 0 to 4 groups independently selected fromhalo or OH, C₁-C₄ alkyleneoxy, C₁-C₄ alkylenethio, C₁-C₄alkyleneoxy-C₁-C₄-alkylene, C₁-C₄-alkylenethio-C₁-C₄-alkylene,—S—C₁-C₄-alkylene, —O—C₁-C₄-alkylene, and C₂-C₆ alkenylene, B isselected from the group consisting of a C₆-C₁₀ aryl, a 5- to 10-memberedheteroaryl, a 4- to 10-membered heterocyclyl containing carbon atoms and1 to 4 additional heteroatoms selected from N, O, and S, a C₃-C₈cycloalkyl which may contain unsaturation and a C₅-C₁₁ spirocycloalkylwhich may contain unsaturation and optionally containing 1 to 3heteroatoms selected from O, N or S, all of which may be optionallysubstituted with one or more R^(b), R^(c), R^(d) and R^(e); R^(b),R^(c), R^(d) and R^(e), at each occurrence, are independently selectedfrom the group consisting of halo, halo-C₁-C₄ alkoxy, OH, CN, NO₂, ═O,NR¹¹R¹², COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkoxycarbonyl,(C═O)NR¹¹R¹², C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄alkylsulfinyl, S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹², N(R¹³)(C═O)OR¹⁴,SO₂R¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹²,O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₃-C₆ cycloalkyl, a 4- to 10-memberedheterocyclyloxy; a C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, CN,hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to10-membered heterocyclyloxy, C₁-C₄-alkylcarbonyloxy and C₁-C₄ alkylthio;—(CHR¹³)_(n)-5- or 6-membered heteroaryl substituted by 0 to 3 groupsindependently selected from the group consisting of halo, C₁-C₄ alkoxy,C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and CF₂CH₃; —(CHR¹³)_(n)-4- to10-membered-heterocyclyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, and CF₂CH₃; di-C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆ cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀arylcarbonyl, C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, and a C₆-C₁₀ arylsubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃; R¹⁰ isselected from the group consisting of C₁-C₄ alkyl, halo, cyano, C₁-C₄alkoxy, and halo-C₁-C₂-alkyl, where halo is F or Cl, R¹¹ and R¹² areindependently, at each occurrence, selected from the group consistingof: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,—(CR¹⁴R¹⁴)_(n)-phenyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH, OCHF₂,di-C₁-C₄-alkylamino, and cyano, —(CHR¹³)_(n)—C₃-C₆-cycloalkylsubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, CF₃, OCF₃, 5- or 6-membered heteroaryl, OH,hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n)-4- to10-membered-heterocyclyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, CF₃, OCF₃, 5- or 6-memberedheteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,—(CHR¹³)_(n)-5- to 10-membered-heteroaryl substituted by 0 to 3 groupsindependently selected from the group consisting of halo, CF₃, OCF₃, 5-or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,di-C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-alkylcarbonylamino-C₁-C₄-alkyl,di-C₁-C₄-alkoxy-C₁-C₄-alkyl, di-C₁-C₄-alkylaminophenyl,hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonyl,C₁-C₄-alkylcarbonyl, phenylcarbonyl;C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkylcarbonyl,di-C₁-C₄-alkylamino-C₁-C₄-alkylcarbonyl, amino-C₁-C₄-alkylcarbonyl, 4-to 10-membered-heterocyclyl-carbonyl, and alternatively, R¹¹ and R¹²,when attached to the same nitrogen, combine to form a 4- to 10-memberedmono- or bicyclic heterocyclic ring containing carbon atoms substitutedby 0 to 3 groups independently selected from the group consisting ofhalo, cyano, CF₃, CHF₂, OCF₃, OCHF₂, OCH₂F, 5- or 6-membered heteroaryl,OH, oxo, hydroxy-C₁-C₄-alkyl, C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2additional heteroatoms selected from N, NR¹³, O and S(O)_(p); R¹³ isindependently, at each occurrence, selected from the group consisting ofH, C₁-C₆ alkyl and —(CH₂)phenyl; R¹⁴ is independently, at eachoccurrence, selected from the group consisting of H, C₁-C₆ alkyl,halo-C₁-C₄-alkyl, C₁-C₄-alkoxycarbonylamino, (C₆-C₁₀ arylcarbonylamino),(a 5- to 10-membered heteroarylcarbonylamino) and —(CH₂)_(n)phenylsubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃,5- or 6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,R⁷ is selected from the group consisting of H, halo, hydroxyl, cyano,oxo, C₁-C₄ alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,halo-C₁-C₄-alkyl, C₁-C₄-alkoxy, and halo-C₁-C₄-alkoxy or R⁶ and R⁷ canbe taken together with the carbons to which they attach to form a C₆-C₁₀aryl ring; n, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5;and p, at each occurrence, is selected from 0, 1 and
 2. 3. The compoundof claim 2, or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate or prodrug thereof, wherein: X¹ is O and X² is CH or N; orX¹ is N and X² is O; or X¹ is N and X² is S; X³, X⁴ and X⁵ are each CR³;W is O; R¹ is independently selected from the group consisting of: halo,C₁-C₄ alkyl, C₁-C₄ alkoxy, and halo-C₁-C₂-alkyl, where halo is F or Cl;R² is H; R³ is selected from the group consisting of H, C₁-C₄ alkoxy,OCF₃, OCHF₂, OCH₂F, and halo-C₁-C₃-alkyl; R⁴ and R⁵ are independentlyselected from H, and C₁-C₆ alkyl;

is selected from the group consisting of a phenyl ring, a 5-memberedheteroaryl ring containing at least one O, N or S atom, or a 6-memberedheteroaryl ring, containing at least one nitrogen atom; R⁶ is selectedfrom the group consisting of H, halo, OCF₃, OCHF₂, OH, CN, NO₂, NR¹¹R¹²,COOH, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl,S(═O)₂NR¹¹R¹², and C₁-C₅ alkyl substituted by 0 to 7 groupsindependently selected from halo, CF₃, OCF₃, OH, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, and C₁-C₄ alkylthio, or R⁶ is B-D-, where D is alinker, which is selected from a single bond, —O—, —S—, O,

C₁-C₄ alkylene, C₁-C₄ alkyleneoxy, C₁-C₄ alkylenethio, C₁-C₄alkyleneoxy-C₁-C₄-alkylene, C₁-C₄-alkylenethio-C₁-C₄-alkylene,—S—C₁-C₄-alkylene, —O—C₁-C₄-alkylene, —NHC(═O)—, —C(═O)NH—, and C₂-C₆alkenylene, B is selected from the group consisting of a C₆-C₁₀ aryl, a5- to 10-membered heteroaryl, a 4- to 10-membered heterocyclylcontaining carbon atoms and 1 to 4 additional heteroatoms selected fromN, O, and S, a C₃-C₈ cycloalkyl which may contain unsaturation and aC₅-C₁₁ spirocycloalkyl which may contain unsaturation and optionallycontaining 1 to 3 heteroatoms selected from O, N or S, all of which maybe optionally substituted with one or more R^(b), R^(c), R^(d) andR^(e); R^(b), R^(c), R^(d) and R^(e), at each occurrence, areindependently selected from the group consisting of halo, halo-C₁-C₄alkoxy, OH, CN, NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy, C₁-C₄ alkylthio,C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄ alkoxy-C₁-C₄ alkoxy, C₁-C₄alkylsulfonyl, C₁-C₄ alkylsulfinyl, S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹¹R¹²,N(R¹³)(C═O)OR¹⁴, SO₂R¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴,O(C═O)NR¹¹R¹², O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, C₃-C₆ cycloalkyl, a 4-to 10-membered heterocyclyloxy; a C₁-C₅ alkyl substituted by 0 to 7groups independently selected from halo, CF₃, OCF₃, OH, CN,hydroxy-C₁-C₄-alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy,di-C₁-C₄-alkylaminophenyl-C₁-C₄-alkyl,(di-C₁-C₄-alkoxy-C₁-C₄-alkyl)-C₁-C₄-alkyl, di-C₁-C₄-alkylamino,C₃-C₆-cycloalkyl, phenyl, C₁-C₄-alkoxyphenyl-C₁-C₄-alkoxy, 4- to10-membered heterocyclyloxy, C₁-C₄-alkylcarbonyloxy and C₁-C₄ alkylthio;—(CHR¹³)_(n)-5- or 6-membered heteroaryl substituted by 0 to 3 groupsindependently selected from the group consisting of halo, C₁-C₄ alkoxy,C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, and CF₂CH₃; —(CHR¹³)_(n)-4- to10-membered-heterocyclyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyclopropyl, CF₃, OCF₃, and CF₂CH₃; di-C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₆ cycloalkyl-C₁-C₄-alkylcarbonyl, C₆-C₁₀arylcarbonyl, C₁-C₄-alkylcarbonyloxy-C₁-C₄-alkyl, and a C₆-C₁₀ arylsubstituted by 0 to 3 groups independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl,C₁-C₄-alkoxycarbonyl, (C═O)NR¹¹R¹², CF₃, OCF₃, and CF₂CH₃; R¹⁰ isselected from the group consisting of C₁-C₄ alkyl, halo, cyano, C₁-C₄alkoxy, and halo-C₁-C₂-alkyl, where halo is F or Cl; R¹¹ and R¹² areindependently, at each occurrence, selected from the group consistingof: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, —(CR¹⁴R¹⁴)_(n)-phenyl substitutedby 0 to 3 groups independently selected from the group consisting ofhalo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or6-membered heteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano,—(CHR¹³)_(n)—C₃-C₆-cycloalkyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, CF₃, OCF₃, 5- or 6-memberedheteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl, —(CHR¹³)_(n)-4- to10-membered-heterocyclyl substituted by 0 to 3 groups independentlyselected from the group consisting of halo, CF₃, OCF₃, 5- or 6-memberedheteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,—(CHR¹³)_(n)-5- to 10-membered-heteroaryl substituted by 0 to 3 groupsindependently selected from the group consisting of halo, CF₃, OCF₃, 5-or 6-membered heteroaryl, OH, hydroxy-C₁-C₄-alkyl, and C₁-C₄ alkyl,hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, andalternatively, R¹¹ and R¹², when attached to the same nitrogen, combineto form a 4- to 10-membered mono- or bicyclic heterocyclic ringcontaining carbon atoms substituted by 0 to 3 groups independentlyselected from the group consisting of halo, cyano, CF₃, CHF₂, OCF₃,OCHF₂, OCH₂F, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C₁-C₄-alkyl,C₁-C₄ alkyl and C₁-C₄ alkoxy, and 0 to 2 additional heteroatoms selectedfrom N, NR¹³, O and S(O)_(p); R¹³ is independently, at each occurrence,selected from the group consisting of H, C₁-C₆ alkyl and —(CH₂)phenyl;R¹⁴ is independently, at each occurrence, selected from the groupconsisting of H, C₁-C₆ alkyl, halo-C₁-C₄-alkyl,C₁-C₄-alkoxycarbonylamino, and —(CH₂)_(n)phenyl substituted by 0 to 3groups independently selected from the group consisting of halo, C₁-C₄alkoxy, C₁-C₄ alkyl, cyclopropyl, CF₃, OCF₃, 5- or 6-memberedheteroaryl, OH, OCHF₂, di-C₁-C₄-alkylamino, and cyano, R⁷ is selectedfrom the group consisting of H, halo, hydroxyl, cyano, oxo, C₁-C₃ alkyl,hydroxy-C₁-C₃-alkyl, and halo-C₁-C₄-alkyl; or R⁶ and R⁷ can be takentogether with the carbons to which they attach to form a C₆-C₁₀ arylring; n, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5; and p,at each occurrence, is selected from 0, 1 and
 2. 4. The compound ofclaim 3, or a stereoisomer, tautomer, pharmaceutically acceptable salt,solvate or prodrug thereof, wherein: X¹ is O and X² is CH; X³, and X⁵are each CH, and X⁴ is CR³; W is O; R¹ is independently selected fromthe group consisting of: CH₃, CH₂CH₃, CF₂CH₃, CHFCH₃, and OCH₃; R² is H;R³ is OCH₃; R⁴ and R⁵ are H;

is selected from the group consisting of phenyl, pyridyl, pyrimidinyl,pyrazinyl, and thiazolyl; R⁶ is selected from the group consisting ofphenyl, cyclopentyl, cyclohexyl, pyridyl, morpholinyl, thiomorpholinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl,tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, oxazolyl, isoxazolyl,pyrazolyl, and imidazolyl, all of which may be optionally substitutedwith one or more R^(b), R^(c), R^(d) and R^(e); R^(b), R^(c), R^(d) andR^(e), at each occurrence, are independently selected from halo,halo-C₁-C₄ alkoxy, OH, CN, NO₂, ═O, NR¹¹R¹², COOH, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkoxycarbonyl, (C═O)NR¹¹R¹², C₁-C₄ alkylsulfonyl,C₁-C₄ alkylsulfinyl, S(═O)₂NR¹¹R¹², N(R¹³)(C═O)NR¹², N(R¹³)(C═O)OR¹⁴,SO₂R¹⁴, N(R¹³)(C═O)R¹⁴, NR¹³S(O)R¹⁴, NR¹³SO₂R¹⁴, O(C═O)NR¹¹R¹²,O(C═O)OR¹⁴, O(C═O)R¹⁴, (C═O)OR¹⁴, and a C₁-C₅ alkyl substituted by 0 to7 groups independently selected from halo and OH; R¹¹ and R¹² areindependently, at each occurrence, selected from the group consistingof: H, C₁-C₄ alkyl, halo-C₁-C₄-alkyl, cyclopropyl, cyclopropylmethyl,hydroxy-C₁-C₄-alkyl, cyano-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,oxetanyl, tetrahydrofuranyl, and alternatively, R¹¹ and R¹², whenattached to the same nitrogen, combine to form an azetidine,pyrrolidine, piperidine, or azepane ring, substituted by 0 to 2 groupsindependently selected from the group consisting of halo, cyano, CF₃,CHF₂, OCF₃, OCHF₂, OCH₂F, OH, oxo, C₁-C₄ alkyl and C₁-C₄ alkoxy; R¹³ isindependently, at each occurrence, selected from the group consisting ofH, and CH₃; R¹⁴ is independently, at each occurrence, selected from thegroup consisting of H, and CH₃; R⁷ is selected from the group consistingof H, F, or CH₃; n, at each occurrence, is selected from 0, 1, or 2; andp, at each occurrence, is selected from 0, 1 and
 2. 5. The compound ofclaim 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt,solvate or prodrug thereof, wherein W is O.
 6. The compound of claim 5,or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor prodrug thereof, wherein the compound of formula I is of Formula Ia.


7. The compound of claim 6, or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:wherein R¹ is C₁₋₃alkyl; W is O; X⁴ is CR³ or CH; R³ is C₁-C₄ alkoxy; R⁴and R⁵ are H;

is phenyl or thiazolyl, wherein the thiazolyl is substituted with R⁶; R⁶is H or B-D: D is a single bond; B is phenyl which may be optionallysubstituted with R^(b); R^(b) is (C═O)NR¹¹R¹²; R¹¹ and R¹² areindependently, at each occurrence, selected from the group consistingof: H, C₁-C₄ alkyl.
 8. The compound of claim 7, or a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof,wherein: R² is H.
 9. The compound of claim 8, or a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof,wherein: R¹ is independently selected from the group consisting of: CH₃and CH₂CH₃.
 10. The compound of claim 9, or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

is selected from the group consisting of phenyl, pyrimidinyl, andthiazolyl; R⁶ is phenyl, morpholinyl, piperidinyl, all of which may beoptionally substituted with one or more R^(b), R^(c), R^(d) and R^(e).11. The compound of claim 10, or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:R^(b), R^(c), R^(d) and R^(e), at each occurrence, are independentlyselected from OH, fluoro, chloro, (C═O)NR¹¹R¹², COOH, and (C═O)OR¹⁴; R¹¹and R¹² are independently, at each occurrence, selected from the groupconsisting of H; C₁-C₄ alkyl, halo-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,oxetanyl, and tetrahydrofuranyl; or R¹³ is independently, at eachoccurrence, selected from the group consisting of H, and CH₃; R¹⁴ isindependently, at each occurrence, selected from the group consisting ofH, and CH₃, and R⁷ is selected from the group consisting of H, F, orCH₃.
 12. The compound as defined in claim 1, wherein the compound orsalt thereof, is selected from6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-ethylimidazo[2,1-b][1,3,4]oxadiazole;4-(4-(((2-(2-ethylimidazo[2,1-b][1,3,4]oxadiazol-6-yl)-6-methoxybenzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide;6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-methylimidazo[2,1-b][1,3,4]oxadiazole;and4-(4-(((6-methoxy-2-(2-methylimidazo[2,1-b][1,3,4]oxadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide.13. A pharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a compound as defined in claim 1, orstereoisomers, tautomers, pharmaceutically acceptable salts, or solvatesthereof, alone or in combination with another therapeutic agent.
 14. Amethod for the treatment of a thromboembolic disorder or the primary orsecondary prophylaxis of a thromboembolic disorder, which comprises thesteps of administering to a patient in need thereof a therapeuticallyeffective amount of a compound as defined in claim 1, or stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof,wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, cerebrovascular thromboembolicdisorders, and thromboembolic disorders in the chambers of the heart orin the peripheral circulation.
 15. A method of inhibiting or preventingplatelet aggregation, which comprises the step of administering to asubject in need thereof a therapeutically effective amount of a PAR4antagonist, as defined in claim 1.